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1
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Trøseid M, Nielsen SD, Vujkovic-Cvijin I. Gut microbiome and cardiometabolic comorbidities in people living with HIV. MICROBIOME 2024; 12:106. [PMID: 38877521 PMCID: PMC11177534 DOI: 10.1186/s40168-024-01815-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 04/12/2024] [Indexed: 06/16/2024]
Abstract
BACKGROUND Despite modern antiretroviral therapy (ART), people living with HIV (PLWH) have increased relative risk of inflammatory-driven comorbidities, including cardiovascular disease (CVD). The gut microbiome could be one of several driving factors, along with traditional risk factors and HIV-related risk factors such as coinfections, ART toxicity, and past immunodeficiency. RESULTS PLWH have an altered gut microbiome, even after adjustment for known confounding factors including sexual preference. The HIV-related microbiome has been associated with cardiometabolic comorbidities, and shares features with CVD-related microbiota profiles, in particular reduced capacity for short-chain fatty acid (SCFA) generation. Substantial inter-individual variation has so far been an obstacle for applying microbiota profiles for risk stratification. This review covers updated knowledge and recent advances in our understanding of the gut microbiome and comorbidities in PLWH, with specific focus on cardiometabolic comorbidities and inflammation. It covers a comprehensive overview of HIV-related and comorbidity-related dysbiosis, microbial translocation, and microbiota-derived metabolites. It also contains recent data from studies in PLWH on circulating metabolites related to comorbidities and underlying gut microbiota alterations, including circulating levels of the SCFA propionate, the histidine-analogue imidazole propionate, and the protective metabolite indole-3-propionic acid. CONCLUSIONS Despite recent advances, the gut microbiome and related metabolites are not yet established as biomarkers or therapeutic targets. The review gives directions for future research needed to advance the field into clinical practice, including promises and pitfalls for precision medicine. Video Abstract.
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Affiliation(s)
- Marius Trøseid
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
- Section for Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Susanne Dam Nielsen
- Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, Copenhagen, 2200, Denmark
- Department of Surgical Gastroenterology and Transplantation, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen Oe, 2100, Denmark
| | - Ivan Vujkovic-Cvijin
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Karsh Division of Gastroenterology & Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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MacCann R, Landay AL, Mallon PWG. HIV and comorbidities - the importance of gut inflammation and the kynurenine pathway. Curr Opin HIV AIDS 2023; 18:102-110. [PMID: 36722199 PMCID: PMC7614535 DOI: 10.1097/coh.0000000000000782] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
PURPOSE OF REVIEW The purpose of this article is to review alterations in microbiota composition, diversity, and functional features in the context of chronic inflammation and comorbidities associated with HIV infection. RECENT FINDINGS The gut microbiome is an important mediator of host immunity, and disruption of gut homeostasis can contribute to both systemic inflammation and immune activation. Ageing and HIV share features of intestinal damage, microbial translocation and alterations in bacterial composition that contribute to a proinflammatory state and development of age-related comorbidities. One such inflammatory pathway reviewed is the nicotinamide adenine dinucleotide (NAD+) producing kynurenine pathway (KP). Kynurenine metabolites regulate many biological processes including host-microbiome communication, immunity and oxidative stress and the KP in turn is influenced by the microbiome environment. Age-associated decline in NAD+ is implicated as a driving factor in many age-associated diseases, including those seen in people with HIV (PWH). Recent studies have shown that KP can influence metabolic changes in PWH, including increased abdominal adiposity and cardiovascular disease. Furthermore, KP activity increases with age in the general population, but it is elevated in PWH at all ages compared to age-matched controls. Host or microbiome-mediated targeting of this pathway has merits to increase healthy longevity and has potential therapeutic applications in PWH. SUMMARY As a growing proportion of PWH age, many face increased risks of developing age-related comorbidities. Chronic inflammation, a pillar of geroscience, the science of ageing and of age-related disease, is influenced by the gut microbiome and its metabolites. Combined, these contribute to a systemic inflammatory signature. Advances in geroscience-based approaches and therapeutics offer a novel paradigm for addressing age-related diseases and chronic inflammation in HIV infection. Whether targeted inhibition of KP activity alleviates pathological conditions or promotes successful ageing in PWH remains to be determined.
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Affiliation(s)
- Rachel MacCann
- UCD Centre for Experimental Pathogen Host Research (CEPHR), School of Medicine, University College Dublin
- St Vincents University Hospital, Elm Park, Dublin 4, Ireland
| | - Alan L Landay
- Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Patrick W G Mallon
- UCD Centre for Experimental Pathogen Host Research (CEPHR), School of Medicine, University College Dublin
- St Vincents University Hospital, Elm Park, Dublin 4, Ireland
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Fragkou PC, Moschopoulos CD, Dimopoulou D, Triantafyllidi H, Birmpa D, Benas D, Tsiodras S, Kavatha D, Antoniadou A, Papadopoulos A. Cardiovascular disease and risk assessment in people living with HIV: Current practices and novel perspectives. Hellenic J Cardiol 2023; 71:42-54. [PMID: 36646212 DOI: 10.1016/j.hjc.2022.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 11/28/2022] [Accepted: 12/31/2022] [Indexed: 01/15/2023] Open
Abstract
Human immunodeficiency virus (HIV) infection represents a major cardiovascular risk factor, and the cumulative cardiovascular disease (CVD) burden among aging people living with HIV (PLWH) constitutes a leading cause of morbidity and mortality. To date, CVD risk assessment in PLWH remains challenging. Therefore, it is necessary to evaluate and stratify the cardiovascular risk in PLWH with appropriate screening and risk assessment tools and protocols to correctly identify which patients are at a higher risk for CVD and will benefit most from prevention measures and timely management. This review aims to accumulate the current evidence on the association between HIV infection and CVD, as well as the risk factors contributing to CVD in PLWH. Furthermore, considering the need for cardiovascular risk assessment in daily clinical practice, the purpose of this review is also to report the current practices and novel perspectives in cardiovascular risk assessment of PLWH and provide further insights into the development and implementation of appropriate CVD risk stratification and treatment strategies, particularly in countries with high HIV burden and limited resources.
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Affiliation(s)
- Paraskevi C Fragkou
- First Department of Critical Care Medicine and Pulmonary Services, Evangelismos Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.
| | - Charalampos D Moschopoulos
- Fourth Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Dimitra Dimopoulou
- Second Department of Pediatrics, Children's Hospital "Panagiotis and Aglaia Kyriakou", National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Helen Triantafyllidi
- Second Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Dionysia Birmpa
- Second Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Dimitrios Benas
- Second Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Sotirios Tsiodras
- First Department of Critical Care Medicine and Pulmonary Services, Evangelismos Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Dimitra Kavatha
- Fourth Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Anastasia Antoniadou
- Fourth Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Antonios Papadopoulos
- Fourth Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
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Ouyang J, Yan J, Zhou X, Isnard S, Harypursat V, Cui H, Routy JP, Chen Y. Relevance of biomarkers indicating gut damage and microbial translocation in people living with HIV. Front Immunol 2023; 14:1173956. [PMID: 37153621 PMCID: PMC10160480 DOI: 10.3389/fimmu.2023.1173956] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 04/10/2023] [Indexed: 05/10/2023] Open
Abstract
The intestinal barrier has the daunting task of allowing nutrient absorption while limiting the entry of microbial products into the systemic circulation. HIV infection disrupts the intestinal barrier and increases intestinal permeability, leading to microbial product translocation. Convergent evidence has shown that gut damage and an enhanced level of microbial translocation contribute to the enhanced immune activation, the risk of non-AIDS comorbidity, and mortality in people living with HIV (PLWH). Gut biopsy procedures are invasive, and are not appropriate or feasible in large populations, even though they are the gold standard for intestinal barrier investigation. Thus, validated biomarkers that measure the degree of intestinal barrier damage and microbial translocation are needed in PLWH. Hematological biomarkers represent an objective indication of specific medical conditions and/or their severity, and should be able to be measured accurately and reproducibly via easily available and standardized blood tests. Several plasma biomarkers of intestinal damage, i.e., intestinal fatty acid-binding protein (I-FABP), zonulin, and regenerating islet-derived protein-3α (REG3α), and biomarkers of microbial translocation, such as lipopolysaccharide (LPS) and (1,3)-β-D-Glucan (BDG) have been used as markers of risk for developing non-AIDS comorbidities in cross sectional analyses and clinical trials, including those aiming at repair of gut damage. In this review, we critically discuss the value of different biomarkers for the estimation of gut permeability levels, paving the way towards developing validated diagnostic and therapeutic strategies to repair gut epithelial damage and to improve overall disease outcomes in PLWH.
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Affiliation(s)
- Jing Ouyang
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Jiangyu Yan
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Xin Zhou
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Stéphane Isnard
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada
- Canadian HIV Trials Network, Canadian Institutes for Health Research, Vancouver, BC, Canada
| | - Vijay Harypursat
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Hongjuan Cui
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Jean-Pierre Routy
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada
- Division of Hematology, McGill University Health Centre, Montréal, QC, Canada
- *Correspondence: Jean-Pierre Routy, ; Yaokai Chen,
| | - Yaokai Chen
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- *Correspondence: Jean-Pierre Routy, ; Yaokai Chen,
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Abstract
PURPOSE OF REVIEW HIV and antiretroviral therapy (ART) use are linked to an increased incidence of atherosclerotic cardiovascular disease (ASCVD). Immune activation persists in ART-treated people with HIV (PWH), and markers of inflammation (i.e. IL-6, C-reactive protein) predict mortality in this population. This review discusses underlying mechanisms that likely contribute to inflammation and the development of ASCVD in PWH. RECENT FINDINGS Persistent inflammation contributes to accelerated ASCVD in HIV and several new insights into the underlying immunologic mechanisms of chronic inflammation in PWH have been made (e.g. clonal haematopoiesis, trained immunity, lipidomics). We will also highlight potential pro-inflammatory mechanisms that may differ in vulnerable populations, including women, minorities and children. SUMMARY Mechanistic studies into the drivers of chronic inflammation in PWH are ongoing and may aid in tailoring effective therapeutic strategies that can reduce ASCVD risk in this population. Focus should also include factors that lead to persistent disparities in HIV care and comorbidities, including sex as a biological factor and social determinants of health. It remains unclear whether ASCVD progression in HIV is driven by unique mediators (HIV itself, ART, immunodeficiency), or if it is an accelerated version of disease progression seen in the general population.
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Affiliation(s)
- Sahera Dirajlal-Fargo
- Rainbow Babies and Children’s Hospital, Cleveland, OH
- Case Western Reserve University, Cleveland, OH
| | - Nicholas Funderburg
- School of Health and Rehabilitation Sciences, The Ohio State University, Columbus, OH
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6
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Butyrate administration is not sufficient to improve immune reconstitution in antiretroviral-treated SIV-infected macaques. Sci Rep 2022; 12:7491. [PMID: 35523797 PMCID: PMC9076870 DOI: 10.1038/s41598-022-11122-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 04/13/2022] [Indexed: 12/15/2022] Open
Abstract
Defective gastrointestinal barrier function and, in turn, microbial translocation have been identified as significant contributors to persistent inflammation in antiretroviral (ARV)-treated people living with HIV. Metabolic supplementation of short-chain fatty acids (SCFAs), generally produced by the commensal microbiome, may improve these outcomes. Butyrate is a SCFA that is essential for the development and maintenance of intestinal immunity and has a known role in supporting epithelial integrity. Herein we assessed whether supplementation with the dietary supplement sodium butyrate would improve immune reconstitution and reduce inflammation in ARV-treated, simian immunodeficiency virus (SIV)-infected rhesus macaques. We demonstrate that butyrate supplementation does not significantly improve immune reconstitution, with no differences observed in systemic CD4+ T-cell frequencies, T-cell functionality or immune activation, microbial translocation, or transcriptional regulation. Our findings demonstrate that oral administration of sodium butyrate is insufficient to reduce persistent inflammation and microbial translocation in ARV-treated, SIV-infected macaques, suggesting that this therapeutic may not reduce co-morbidities and co-mortalities in treated people living with HIV.
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McCutcheon K, Manga P. Human Immunodeficiency Virus and Cardiovascular Disease: Revisiting the Inflammation-Thrombosis Axis. Thromb Haemost 2022; 122:476-479. [PMID: 34689321 DOI: 10.1055/s-0041-1736445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Affiliation(s)
- Keir McCutcheon
- Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa
| | - Pravin Manga
- Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa
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8
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Masters MC, Landay AL, Robbins PD, Tchkonia T, Kirkland JL, Kuchel GA, Niedernhofer LJ, Palella FJ. Chronic HIV Infection and Aging: Application of a Geroscience-Guided Approach. J Acquir Immune Defic Syndr 2022; 89:S34-S46. [PMID: 35015744 PMCID: PMC8751288 DOI: 10.1097/qai.0000000000002858] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 09/27/2021] [Indexed: 12/16/2022]
Abstract
ABSTRACT The ability of virally suppressive antiretroviral therapy use to extend the life span of people with HIV (PWH) implies that the age of PWH will also increase. Among PWH, extended survival comes at a cost of earlier onset and increased rates of aging-associated comorbidities and geriatric syndromes, with persistent inflammation and immune dysregulation consequent to chronic HIV infection and to antiretroviral therapy use contributing to an overall decrease in health span. The geroscience hypothesis proposes that the root causes of most aging-related chronic diseases and conditions is the aging process itself. Hence, therapeutically targeting fundamental aging processes could have a greater impact on alleviating or delaying aging-associated comorbidities than addressing each disease individually. Extending the geroscience hypothesis to PWH, we speculate that targeting basic mechanisms of aging will improve overall health with age. Clinical features and pathophysiologic mechanisms of chronic diseases in PWH qualitatively resemble those seen in older adults without HIV. Therefore, drugs that target any of the pillars of aging, including metformin, rapamycin, and nicotinamide adenine dinucleotide precursors, may also slow the rate of onset of age-associated comorbidities and geriatric syndromes in PWH. Drugs that selectively induce apoptosis of senescent cells, termed senolytics, may also improve health span among PWH. Preliminary evidence suggests that senescent cell burden is increased in PWH, implying that senescent cells are an excellent therapeutic target for extending health span. Recently initiated clinical trials evaluating senolytics in age-related diseases offer insights into the design and potential implementation of similar trials for PWH.
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Affiliation(s)
- Mary C. Masters
- Department of Medicine, Division of Infectious Diseases, Northwestern University, Chicago, IL
| | - Alan L. Landay
- Department of Internal Medicine, Section of Geriatric Medicine Rush University Medical Center, Chicago, IL
| | - Paul D. Robbins
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN
| | - Tamar Tchkonia
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN; and
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN; and
| | - James L. Kirkland
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN; and
| | | | - Laura J. Niedernhofer
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN
| | - Frank J. Palella
- Department of Medicine, Division of Infectious Diseases, Northwestern University, Chicago, IL
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9
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Bourke CD, Prendergast AJ. The Anti-inflammatory Effects of Cotrimoxazole Prophylaxis for People Living With Human Immunodeficiency Virus in Sub-Saharan Africa. J Infect Dis 2021; 222:347-350. [PMID: 31714953 DOI: 10.1093/infdis/jiz495] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 10/30/2019] [Indexed: 11/13/2022] Open
Affiliation(s)
- Claire D Bourke
- Blizard Institute, Queen Mary University of London, London, United Kingdom.,Zviambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | - Andrew J Prendergast
- Blizard Institute, Queen Mary University of London, London, United Kingdom.,Zviambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
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10
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Utay NS, Overton ET. Immune Activation and Inflammation in People With Human Immunodeficiency Virus: Challenging Targets. J Infect Dis 2021; 221:1567-1570. [PMID: 31282534 DOI: 10.1093/infdis/jiz351] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 07/04/2019] [Indexed: 12/13/2022] Open
Affiliation(s)
- Netanya S Utay
- Division of General Internal Medicine, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston
| | - Edgar T Overton
- Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham School of Medicine
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Abstract
The usage of combination antiretroviral therapy in people with HIV (PWH) has incited profound improvement in morbidity and mortality. Yet, PWH may not experience full restoration of immune function which can manifest with non-AIDS comorbidities that frequently associate with residual inflammation and can imperil quality of life or longevity. In this review, we discuss the pathogenesis underlying chronic inflammation and residual immune dysfunction in PWH, as well as potential therapeutic interventions to ameliorate them and prevent incidence or progression of non-AIDS comorbidities. Current evidence advocates that early diagnosis and prompt initiation of therapy at high CD4 counts may represent the best available approach for an improved immune recovery in PWH.
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Affiliation(s)
- Catherine W Cai
- HIV Pathogenesis Section, Laboratory of Immunoregulation, NIAID, NIH, United States
| | - Irini Sereti
- HIV Pathogenesis Section, Laboratory of Immunoregulation, NIAID, NIH, United States.
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12
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Dysfunctional Immunometabolism in HIV Infection: Contributing Factors and Implications for Age-Related Comorbid Diseases. Curr HIV/AIDS Rep 2020; 17:125-137. [PMID: 32140979 DOI: 10.1007/s11904-020-00484-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
PURPOSE OF REVIEW An increasing body of evidence indicates that persons living with HIV (PLWH) display dysfunctional immunometabolism. Here, we provide an updated review of this topic and its relationship to HIV-associated immune stimuli and age-related disease. RECENT FINDINGS HIV infection alters immunometabolism by increasing reliance on aerobic glycolysis for energy and productive infection and repurposing oxidative phosphorylation machinery for immune cell proliferation and survival. Recent studies in PLWH with diabetes mellitus or cardiovascular disease have identified an association with elevated T cell and monocyte glucose metabolism, respectively. Immunometabolic dysfunction has also been observed in PLWH in frailty and additional studies suggest a role for immunometabolism in non-AIDS defining cancers and neurocognitive disease. There is a plethora of HIV-associated immune stimuli that could drive immunometabolic dysfunction and age-related disease in PLWH, but studies directly examining their relationship are lacking. Immunometabolic dysfunction is characteristic of HIV infection and is a potential link between HIV-associated stimuli and age-related comorbidities.
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Rosel-Pech C, Chávez-Torres M, Bekker-Méndez VC, Pinto-Cardoso S. Therapeutic avenues for restoring the gut microbiome in HIV infection. Curr Opin Pharmacol 2020; 54:188-201. [PMID: 33271427 DOI: 10.1016/j.coph.2020.09.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 09/11/2020] [Accepted: 09/24/2020] [Indexed: 02/07/2023]
Abstract
The interplay between the gut microbiota, the intestinal barrier and the mucosal immune system is profoundly altered in Human Immunodeficiency Virus (HIV) infection. An HIV-associated microbial dysbiotic signature has been difficult to define due to the strong impact of confounders that are intimately linked with HIV infection, namely HIV risk behaviors. When controlling for sexual preference and gender, HIV-associated microbial dysbiotic signatures are characterized by an increase in deleterious taxa and a decrease in beneficial bacteria and their respective metabolic end-products. First attempts to restore the gut microbiota of HIV subjects on Antiretroviral Therapy using Fecal Microbiota Transplantation proved to be safe and reported mild transient engraftment of donor microbiota and no effect on markers of HIV disease progression. This review focuses on the current evidence supporting a role for microbial dysbiosis in HIV pathogenesis, and reviews current microbiome-based therapeutics for restoring the gut microbiota in HIV infection.
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Affiliation(s)
- Cecilia Rosel-Pech
- Unidad de Investigación Médica en Inmunología e Infectología, Hospital de Infectología "Dr. Daniel Méndez Hernández", Centro Médico Nacional "La Raza", IMSS, Ciudad de México, Mexico; Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Monserrat Chávez-Torres
- Centro de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Ciudad de México, Mexico; Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, Mexico
| | - Vilma Carolina Bekker-Méndez
- Unidad de Investigación Médica en Inmunología e Infectología, Hospital de Infectología "Dr. Daniel Méndez Hernández", Centro Médico Nacional "La Raza", IMSS, Ciudad de México, Mexico
| | - Sandra Pinto-Cardoso
- Centro de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Ciudad de México, Mexico.
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14
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Blanco JR, Negredo E, Bernal E, Blanco J. Impact of HIV infection on aging and immune status. Expert Rev Anti Infect Ther 2020; 19:719-731. [PMID: 33167724 DOI: 10.1080/14787210.2021.1848546] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Introduction: Thanks to antiretroviral therapy (ART), persons living with HIV (PLWH), have a longer life expectancy. However, immune activation and inflammation remain elevated, even after viral suppression, and contribute to morbidity and mortality in these individuals.Areas covered: We review aspects related to immune activation and inflammation in PLWH, their consequences, and the potential strategies to reduce immune activation in HIV-infected individuals on ART.Expert opinion: When addressing a problem, it is necessary to thoroughly understand the topic. This is the main limitation faced when dealing with immune activation and inflammation in PLWH since there is no consensus on the ideal markers to evaluate immune activation or inflammation. To date, the different interventions that have addressed this problem by targeting specific mediators have not been able to significantly reduce immune activation or its consequences. Given that there is currently no curative intervention for HIV infection, more studies are necessary to understand the mechanism underlying immune activation and help to identify potential therapeutic targets that contribute to improving the life expectancy of HIV-infected individuals.
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Affiliation(s)
- Jose-Ramon Blanco
- Servicio de Enfermedades Infecciosas, Hospital Universitario San Pedro- Centro De Investigación Biomédica De La Rioja (CIBIR), La Rioja, Spain
| | - Eugenia Negredo
- Lluita Contra La Sida Foundation, Germans Trias I Pujol University Hospital, Badalona, Spain. Centre for Health and Social Care Research (CESS), Faculty of Medicine, University of Vic - Central University of Catalonia (Uvic - UCC), Catalonia, Spain
| | - Enrique Bernal
- Unidad De Enfermedades Infecciosas, Hospital General Universitario Reina Sofía, Universidad De Murcia, Murcia, Spain
| | - Juliá Blanco
- AIDS Research Institute-IrsiCaixa, Badalona, Barcelona, Spain.,Universitat De Vic-Central De Catalunya (UVIC-UCC), Vic, Spain
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15
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Kettelhut A, Bowman E, Funderburg NT. Immunomodulatory and Anti-Inflammatory Strategies to Reduce Comorbidity Risk in People with HIV. Curr HIV/AIDS Rep 2020; 17:394-404. [PMID: 32535769 DOI: 10.1007/s11904-020-00509-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE OF REVIEW In this review, we will discuss treatment interventions targeting drivers of immune activation and chronic inflammation in PWH. RECENT FINDINGS Potential treatment strategies to prevent the progression of comorbidities in PWH have been identified. These studies include, among others, the use of statins to modulate lipid alterations and subsequent innate immune receptor activation, probiotics to restore healthy gut microbiota and reduce microbial translocation, hydroxychloroquine to reduce immune activation by altering Toll-like receptors function and expression, and canakinumab to block the action of a major pro-inflammatory cytokine IL-1β. Although many of the treatment strategies discussed here show promise, due to the complex nature of chronic inflammation and comorbidities in PWH, larger clinical studies are needed to understand and target the prominent drivers and inflammatory cascades underlying these end-organ diseases.
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Affiliation(s)
- Aaren Kettelhut
- Division of Medical Laboratory Science, School of Health and Rehabilitation Sciences, Ohio State University College of Medicine, Columbus, OH, USA
| | - Emily Bowman
- Division of Medical Laboratory Science, School of Health and Rehabilitation Sciences, Ohio State University College of Medicine, Columbus, OH, USA
| | - Nicholas T Funderburg
- Division of Medical Laboratory Science, School of Health and Rehabilitation Sciences, Ohio State University College of Medicine, Columbus, OH, USA.
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Macatangay BJC, Jackson EK, Abebe KZ, Comer D, Cyktor J, Klamar-Blain C, Borowski L, Gillespie DG, Mellors JW, Rinaldo CR, Riddler SA. A Randomized, Placebo-Controlled, Pilot Clinical Trial of Dipyridamole to Decrease Human Immunodeficiency Virus-Associated Chronic Inflammation. J Infect Dis 2020; 221:1598-1606. [PMID: 31282542 PMCID: PMC7184919 DOI: 10.1093/infdis/jiz344] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 07/04/2019] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Adenosine is a potent immunoregulatory nucleoside produced during inflammatory states to limit tissue damage. We hypothesized that dipyridamole, which inhibits cellular adenosine uptake, could raise the extracellular adenosine concentration and dampen chronic inflammation associated with human immunodeficiency virus (HIV) type 1. METHODS Virally suppressed participants receiving antiretroviral therapy were randomized 1:1 for 12 weeks of dipyridamole (100 mg 4 times a day) versus placebo capsules. All participants took open-label dipyridamole during weeks 12-24. Study end points included changes in markers of systemic inflammation (soluble CD163 and CD14, and interleukin 6) and levels of T-cell immune activation (HLA-DR+CD38+). RESULTS Of 40 participants who were randomized, 17 dipyridamole and 18 placebo recipients had baseline and week 12 data available for analyses. There were no significant changes in soluble markers, apart from a trend toward decreased levels of soluble CD163 levels (P = .09). There was a modest decrease in CD8+ T-cell activation (-17.53% change for dipyridamole vs +13.31% for placebo; P = .03), but the significance was lost in the pooled analyses (P = .058). Dipyridamole also reduced CD4+ T-cell activation (-11.11% change; P = .006) in the pooled analyses. In post hoc analysis, detectable plasma dipyridamole levels were associated with higher levels of inosine, an adenosine surrogate, and of cyclic adenosine monophosphate. CONCLUSION Dipyridamole increased extracellular adenosine levels and decreased T-cell activation significantly among persons with HIV-1 infection receiving virally suppressive therapy.
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Affiliation(s)
- Bernard J C Macatangay
- Department of Medicine, University of Pittsburgh School of Medicine, Pennsylvania
- Department of Infectious Diseases and Microbiology, University of Pittsburgh Graduate School of Public Health, Pennsylvania
| | - Edwin K Jackson
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pennsylvania
| | - Kaleab Z Abebe
- Department of Medicine, University of Pittsburgh School of Medicine, Pennsylvania
| | - Diane Comer
- Department of Medicine, University of Pittsburgh School of Medicine, Pennsylvania
| | - Joshua Cyktor
- Department of Medicine, University of Pittsburgh School of Medicine, Pennsylvania
| | - Cynthia Klamar-Blain
- Department of Medicine, University of Pittsburgh School of Medicine, Pennsylvania
| | - Luann Borowski
- Department of Infectious Diseases and Microbiology, University of Pittsburgh Graduate School of Public Health, Pennsylvania
| | - Delbert G Gillespie
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pennsylvania
| | - John W Mellors
- Department of Medicine, University of Pittsburgh School of Medicine, Pennsylvania
- Department of Infectious Diseases and Microbiology, University of Pittsburgh Graduate School of Public Health, Pennsylvania
| | - Charles R Rinaldo
- Department of Infectious Diseases and Microbiology, University of Pittsburgh Graduate School of Public Health, Pennsylvania
- Department of Pathology, University of Pittsburgh School of Medicine, Pennsylvania
| | - Sharon A Riddler
- Department of Medicine, University of Pittsburgh School of Medicine, Pennsylvania
- Department of Infectious Diseases and Microbiology, University of Pittsburgh Graduate School of Public Health, Pennsylvania
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17
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Brief Report: No Evidence for an Association Between Statin Use and Lower Biomarkers of HIV Persistence or Immune Activation/Inflammation During Effective ART. J Acquir Immune Defic Syndr 2020; 82:e27-e31. [PMID: 31335587 DOI: 10.1097/qai.0000000000002124] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Statins exert pleiotropic anti-inflammatory and immune-modulatory effects, which might translate into antiviral activity. We evaluated whether reported current statin exposure is associated with lower levels of markers of HIV persistence and immune activation/inflammation. METHODS We compared levels of markers of HIV viral persistence [cell-associated HIV RNA (CA-RNA), CA-DNA, and single copy assay plasma HIV RNA] and immune activation/inflammation (IL-6, IP-10, neopterin, sCD14, sCD163, and TNF-alpha) between statin users and nonusers among participants of ACTG A5321 who initiated antiretroviral therapy (ART) during chronic infection and maintained virologic suppression (HIV-1 RNA levels ≤50 copies/mL) for ≥3 years. RESULTS A total of 303 participants were analyzed. Median time on the current statin was 2.9 years (1.2-5.1). There were no differences between statin users and nonusers in levels of CA-DNA (median 650 vs. 540 copies/10 CD4 T cells; P = 0.58), CA-RNA (53 vs. 37 copies/10 CD4 T cells; P = 0.12), or single copy assay (0.4 vs. 0.4 copies/mL; P = 0.45). Similarly, there were no significant differences between statin users and nonusers in markers of inflammation/activation, except for IP-10 (137 vs. 118 pg/mL; P = 0.028). Findings were unchanged after adjustment for factors including pre-ART CD4 and HIV RNA, and years on ART. CONCLUSIONS In this cohort of persons on long-term suppressive ART, current statin use was not associated with lower levels of HIV persistence or immune activation/inflammation. These results do not support a major role for statins in reducing HIV persistence, although an early transient effect cannot be excluded. Prospective, randomized studies are needed to confirm these findings.
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18
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Luján JA, Rugeles MT, Taborda NA. Contribution of the Microbiota to Intestinal Homeostasis and its Role in the Pathogenesis of HIV-1 Infection. Curr HIV Res 2020; 17:13-25. [PMID: 30854974 DOI: 10.2174/1570162x17666190311114808] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 02/25/2019] [Accepted: 03/06/2019] [Indexed: 12/18/2022]
Abstract
During HIV infection, massive destruction of CD4+ T cells ensues, preferentially depleting the Th17 subset at the gut-associated lymphoid tissue (GALT), leading to a loss of mucosal integrity and an increase in cell permeability. This process favors microbial translocation between the intestinal lumen and the circulatory system, contributing to persistent immune activation and chronic inflammation characteristic of HIV infection. Thus, the gut microbiota plays an integral role in maintaining the structure and function of the mucosal barrier, a critical factor for immune homeostasis. However, in the context of HIV infection, changes in the gut microbiota have been reported and have been linked to disease progression. Here, we review evidence for the role of the gut microbiota in intestinal homeostasis, its contribution to HIV pathogenesis, as well as its use in the development of therapeutic strategies.
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Affiliation(s)
- Jorge A Luján
- Grupo Inmunovirologia, Facultad de Medicina. Universidad de Antioquia, Medellin, Colombia
| | - Maria T Rugeles
- Grupo Inmunovirologia, Facultad de Medicina. Universidad de Antioquia, Medellin, Colombia
| | - Natalia A Taborda
- Grupo Inmunovirologia, Facultad de Medicina. Universidad de Antioquia, Medellin, Colombia.,Grupo de Investigaciones Biomédicas, Facultad de Ciencias de la Salud, Corporación Universitaria Remington, Medellín, Colombia
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19
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Abstract
PURPOSE OF REVIEW This article describes the use of biomarkers in expanding our understanding of chronic non-AIDS comorbidities among persons living with HIV (PLWH) receiving antiretroviral therapy (ART). RECENT FINDINGS We review current evidence that biomarkers of chronic immune activation and inflammation associate with a broad spectrum of end-organ diseases in PLWH. We discuss how ART may impact inflammation associated with HIV infection and the degree to which inflammation persists despite effective suppression of viral replication in plasma. We then discuss the limitations of the current literature, which lacks evidence of causality and disproportionately involves a few protein biomarkers that are unable to disentangle complex and overlapping biological pathways. SUMMARY Premature end-organ disease among PLWH has been repeatedly associated with higher levels of blood biomarkers reflecting inflammation and immune activation, which, despite viral suppression and CD4 T-cell increases after ART treatment, remain elevated relative to uninfected persons. There remain important unanswered questions with implications for the development of anti-inflammatory treatment strategies aimed at mitigating excess risk for end-organ comorbidities among PLWH.
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20
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Borato DCK, Vellosa JCR. Association between soluble biomarkers - microbial translocation, inflammation and cardiovascular risk in HIV- infected individuals: a systematic review. BRAZ J PHARM SCI 2020. [DOI: 10.1590/s2175-97902019000318567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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21
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Abstract
Antiretroviral therapy has largely transformed HIV infection into a chronic disease condition. As such, physicians and other providers caring for individuals living with HIV infection need to be aware of the potential cardiovascular complications of HIV infection and the nuances of how HIV infection increases the risk of cardiovascular diseases, including acute myocardial infarction, stroke, peripheral artery disease, heart failure and sudden cardiac death, as well as how to select available therapies to reduce this risk. In this Review, we discuss the epidemiology and clinical features of cardiovascular disease, with a focus on coronary heart disease, in the setting of HIV infection, which includes a substantially increased risk of myocardial infarction even when the HIV infection is well controlled. We also discuss the mechanisms underlying HIV-associated atherosclerotic cardiovascular disease, such as the high rates of traditional cardiovascular risk factors in patients with HIV infection and HIV-related factors, including the use of antiretroviral therapy and chronic inflammation in the setting of effectively treated HIV infection. Finally, we highlight available therapeutic strategies, as well as approaches under investigation, to reduce the risk of cardiovascular disease and lower inflammation in patients with HIV infection.
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Affiliation(s)
- Priscilla Y Hsue
- University of California-San Francisco, Zuckerberg San Francisco General Hospital, San Francisco, CA, USA.
| | - David D Waters
- University of California-San Francisco, Zuckerberg San Francisco General Hospital, San Francisco, CA, USA
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22
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Kavanagh K, Hsu FC, Davis AT, Kritchevsky SB, Rejeski WJ, Kim S. Biomarkers of leaky gut are related to inflammation and reduced physical function in older adults with cardiometabolic disease and mobility limitations. GeroScience 2019; 41:923-933. [PMID: 31654268 DOI: 10.1007/s11357-019-00112-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 10/09/2019] [Indexed: 12/14/2022] Open
Abstract
Intestinal barrier dysfunction is hypothesized to be a contributing determinant of two prominent characteristics of aging: inflammation and decline in physical function. A relationship between microbial translocation (MT), or their biomarkers (lipopolysaccharide binding protein-1 [LBP-1], soluble cluster of differentiation [sCD]-14), and physical function has been reported in healthy older adults, rats, and invertebrates. However, it is not known whether the existence of comorbidities, or clinical interventions intended to reduce comorbidities through weight loss or exercise, alters this connection. We measured inflammation, MT, and physical function in 288 overweight/obese older patients with cardiometabolic disease and self-reported mobility limitations who were enrolled in a weight loss and lifestyle intervention study. At baseline, inflammatory cytokines and LBP-1 were positively correlated after adjustment for age, gender, and body mass index. A higher LBP-1 was significantly associated with poorer physical functional after covariate adjustment. Further, even when IL-6 levels were included in the models, 400-m walk time (p = 0.003), short physical performance battery (p = 0.07), and IL-8 (p < 0.001) remained positively associated with LBP-1. Lifestyle interventions improved body mass and some functional measures; however, MT and inflammation were unchanged. MT is reliably related to inflammation, and to poorer physical function in older adults with comorbid conditions. Intestinal barrier function did not appear to improve as a result of intervention assignment, suggesting alternative strategies are needed to target this pro-inflammatory pathway in aging.
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Affiliation(s)
- Kylie Kavanagh
- Department of Pathology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157-1009, USA. .,School of Medicine, University of Tasmania, TAS, Hobart, Australia.
| | - Fang-Chi Hsu
- Division of Public Health Sciences, Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Ashley T Davis
- Department of Pathology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157-1009, USA
| | - Stephen B Kritchevsky
- Sticht Center on Healthy Aging and Alzheimer's Prevention, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - W Jack Rejeski
- Department of Health and Exercise Science, Wake Forest University, Winston-Salem, NC, USA
| | - Sunghye Kim
- Department of Internal Medicine, Section of Rheumatology, Wake Forest School of Medicine, Winston-Salem, NC, USA
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23
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Effect of Lactobacillus rhamnosus GG Supplementation on Intestinal Inflammation Assessed by PET/MRI Scans and Gut Microbiota Composition in HIV-Infected Individuals. J Acquir Immune Defic Syndr 2019; 78:450-457. [PMID: 29874201 DOI: 10.1097/qai.0000000000001693] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Alterations in the gut microbiome have been associated with inflammation and increased cardiovascular risk in HIV-infected individuals. The aim of this study was to investigate the effects of the probiotic strain Lactobacillus rhamnosus GG (LGG) on intestinal inflammation, gut microbiota composition, and systemic markers of microbial translocation and inflammation in HIV-infected individuals. METHODS This prospective, clinical interventional trial included 45 individuals [15 combination antiretroviral treatment (cART) naive and 30 cART treated] who ingested LGG twice daily at a dosage of 6 × 109 colony-forming units per capsule for a period of 8 weeks. Intestinal inflammation was assessed using F-2-fluoro-2-deoxy-D-glucose positron emission tomography/magnetic resonance imaging (F-FDG PET/MRI) scans in 15 individuals. Gut microbiota composition (V3-V4 region of the 16s rRNA gene) and markers of microbial translocation and inflammation (lipopolysaccharide, sCD14, sCD163, sCD25, high-sensitive CRP, IL-6, and tumor necrosis factor-alpha) were analyzed at baseline and after intervention. RESULTS At baseline, evidence of intestinal inflammation was found in 75% of the participants, with no significant differences between cART-naive and cART-treated individuals. After LGG supplementation, a decrease in intestinal inflammation was detected on PET/MRI (-0.3 mean difference in the combined activity grade score from 6 regions, P = 0.006), along with a reduction of Enterobacteriaceae (P = 0.018) and Erysipelotrichaceae (P = 0.037) in the gut microbiome, with reduced Enterobacteriaceae among individuals with decreased F-FDG uptake on PET/MRI (P = 0.048). No changes were observed for soluble markers of microbial translocation and inflammation. CONCLUSIONS A decrease in intestinal inflammation was found in HIV-infected individuals after ingestion of LGG along with a reduced abundance of Enterobacteriaceae, which may explain the local anti-inflammatory effect in the gut.
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24
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Feinstein MJ, Hsue PY, Benjamin L, Bloomfield GS, Currier JS, Freiberg MS, Grinspoon SK, Levin J, Longenecker CT, Post. WS. Characteristics, Prevention, and Management of Cardiovascular Disease in People Living With HIV: A Scientific Statement From the American Heart Association. Circulation 2019; 140:e98-e124. [PMID: 31154814 PMCID: PMC7993364 DOI: 10.1161/cir.0000000000000695] [Citation(s) in RCA: 421] [Impact Index Per Article: 70.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
As early and effective antiretroviral therapy has become more widespread, HIV has transitioned from a progressive, fatal disease to a chronic, manageable disease marked by elevated risk of chronic comorbid diseases, including cardiovascular diseases (CVDs). Rates of myocardial infarction, heart failure, stroke, and other CVD manifestations, including pulmonary hypertension and sudden cardiac death, are significantly higher for people living with HIV than for uninfected control subjects, even in the setting of HIV viral suppression with effective antiretroviral therapy. These elevated risks generally persist after demographic and clinical risk factors are accounted for and may be partly attributed to chronic inflammation and immune dysregulation. Data on long-term CVD outcomes in HIV are limited by the relatively recent epidemiological transition of HIV to a chronic disease. Therefore, our understanding of CVD pathogenesis, prevention, and treatment in HIV relies on large observational studies, randomized controlled trials of HIV therapies that are underpowered to detect CVD end points, and small interventional studies examining surrogate CVD end points. The purpose of this document is to provide a thorough review of the existing evidence on HIV-associated CVD, in particular atherosclerotic CVD (including myocardial infarction and stroke) and heart failure, as well as pragmatic recommendations on how to approach CVD prevention and treatment in HIV in the absence of large-scale randomized controlled trial data. This statement is intended for clinicians caring for people with HIV, individuals living with HIV, and clinical and translational researchers interested in HIV-associated CVD.
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Affiliation(s)
| | - Priscilla Y. Hsue
- University of California-San Francisco School of Medicine, San Francisco, CA
| | | | | | - Judith S. Currier
- University of California-Los Angeles School of Medicine, Los Angeles, CA
| | | | | | - Jules Levin
- National AIDS Treatment Advocacy Program, New York, NY
| | | | - Wendy S. Post.
- Johns Hopkins University School of Medicine, Baltimore, MD
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25
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Reid M, Ma Y, Scherzer R, Price JC, French AL, Huhn GD, Plankey MW, Peters M, Grunfeld C, Tien PC. Contribution of Liver Fibrosis and Microbial Translocation to Immune Activation in Persons Infected With HIV and/or Hepatitis C Virus. J Infect Dis 2019; 217:1289-1297. [PMID: 29304196 DOI: 10.1093/infdis/jix688] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 01/02/2018] [Indexed: 12/26/2022] Open
Abstract
Background The independent contributions of microbial translocation and liver fibrosis to immune activation in human immunodeficiency virus (HIV) and/or hepatitis C virus (HCV)-infected persons are unclear. Methods Multivariable linear regression was used to evaluate whether intestinal fatty acid binding protein (I-FABP: a marker of gut epithelial integrity) and transient elastography-measured liver fibrosis might mediate the association of HIV and HCV with the soluble CD14 (sCD14) level in 120 individuals with HIV and HCV coinfection, 262 with HIV monoinfection, 72 with HCV monoinfection, and 170 without infection. Results Coinfected individuals, HIV-monoinfected individuals, and HCV-monoinfected individuals had 37%, 21%, and 12% higher sCD14 levels, respectively, than uninfected individuals, after multivariable adjustment. Additional adjustment for I-FABP level modestly attenuated the association of HIV infection, but attenuation occurred to a lesser extent in the HCV-monoinfected group. Adjustment for liver fibrosis substantially attenuated the association of HCV infection, but attenuation occurred to a lesser extent in the HIV-monoinfected group. Relative to the uninfected group, the primary mediator of the sCD14 level was the I-FABP level in the HIV-infected groups and liver fibrosis in the HCV-monoinfected group. Conclusion HIV and HCV are independently and additively associated with higher a sCD14 level. Our findings suggest that microbial translocation contributes to an increased sCD14 level during HIV infection, whereas liver fibrosis plays a stronger role during HCV monoinfection. Coinfected persons may be at greatest risk for progression, because of the independent effects of microbial translocation and liver fibrosis on immune activation.
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Affiliation(s)
- Michael Reid
- Department of Medicine, University of California-San Francisco, California
| | - Yifei Ma
- Department of Medicine, University of California-San Francisco, California
| | - Rebecca Scherzer
- Department of Medicine, University of California-San Francisco, California.,Medical Service, Department of Veteran Affairs Medical Center, San Francisco, California
| | - Jennifer C Price
- Department of Medicine, University of California-San Francisco, California
| | - Audrey L French
- Department of Medicine, Stroger Hospital and Rush University, Chicago, Illinois
| | - Gregory D Huhn
- Department of Medicine, Stroger Hospital and Rush University, Chicago, Illinois
| | - Michael W Plankey
- Department of Medicine, Georgetown University Medical Center, Washington, D.C
| | - Marion Peters
- Department of Medicine, University of California-San Francisco, California
| | - Carl Grunfeld
- Department of Medicine, University of California-San Francisco, California.,Medical Service, Department of Veteran Affairs Medical Center, San Francisco, California
| | - Phyllis C Tien
- Department of Medicine, University of California-San Francisco, California.,Medical Service, Department of Veteran Affairs Medical Center, San Francisco, California
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26
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Crakes KR, Jiang G. Gut Microbiome Alterations During HIV/SIV Infection: Implications for HIV Cure. Front Microbiol 2019; 10:1104. [PMID: 31191468 PMCID: PMC6539195 DOI: 10.3389/fmicb.2019.01104] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 04/30/2019] [Indexed: 12/11/2022] Open
Abstract
Gut mucosal damage, associated with Human Immunodeficiency Virus-1 (HIV) infection, is characterized by depletion in CD4+ T cells and persistent immune activation as a result of early epithelial barrier disruption and systemic translocation of microbial products. Unique approaches in studying both HIV infection in human patients and Simian Immunodeficiency Virus (SIV) infection in rhesus macaques have provided critical evidence for the pathogenesis and treatment of HIV/AIDS. While there is vast resemblance between SIV and HIV infection, the development of gut dysbiosis attributed to HIV infection in chronically infected patients has not been consistently reported in SIV infection in the non-human primate model of AIDS, raising concerns for the translatability of gut microbiome studies in rhesus macaques. This review outlines our current understanding of gut microbial signatures across various stages of HIV versus SIV infection, with an emphasis on the impact of microbiome-based therapies in restoring gut mucosal immunity as well as their translational potential to supplement current HIV cure efforts.
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Affiliation(s)
- Katti R. Crakes
- Department of Medical Microbiology and Immunology, University of California, Davis, Davis, CA, United States
| | - Guochun Jiang
- Department of Biochemistry and Biophysics, Institute for Global Health & Infectious Diseases, UNC HIV Cure Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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27
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Utay NS, Somasunderam A, Hinkle JE, Petschow BW, Detzel CJ, Somsouk M, Fichtenbaum CJ, Weaver EM, Shaw AL, Asmuth DM. Serum Bovine Immunoglobulins Improve Inflammation and Gut Barrier Function in Persons with HIV and Enteropathy on Suppressive ART. Pathog Immun 2019; 4:124-146. [PMID: 31139758 PMCID: PMC6508431 DOI: 10.20411/pai.v4i1.276] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 04/08/2019] [Indexed: 12/11/2022] Open
Abstract
Background Systemic inflammation persists in chronic HIV infection and is associated with increased rates of non-AIDS events such as cardiovascular and liver disease. Increased gut permeability and systemic exposure to microbial products are key drivers of this inflammation. Serum-derived bovine immunoglobulin/protein isolate (SBI) supports gut healing in other conditions such as inflammatory bowel disease. Methods In this randomized, double-blind study, participants receiving suppressive antiretroviral therapy (ART) with chronic diarrhea received placebo or SBI at 2.5 g BID or 5 g BID for 4 weeks, followed by a 20-week placebo-free extension phase with SBI at either 2.5 or 5 g BID. Intestinal fatty acid binding protein (I-FABP), zonulin, flagellin, lipopolysaccharide (LPS) and LPS-binding protein, and inflammatory markers were measured by ELISA or multiplex assays. Non-parametric tests were used for analysis. Results One hundred three participants completed the study. By week 24 SBI significantly decreased circulating levels of I-FABP (-0.35 ng/μL, P=0.002) and zonulin (-4.90 ng/μL, P=0.003), suggesting improvement in gut damage, and interleukin-6 (IL-6) (-0.40 pg/μL, P=0.002), reflecting improvement in systemic inflammation. In participants with the lowest quartile of CD4+ T-cell counts at baseline (189-418 cells/μL), CD4+ T-cell counts increased significantly (26 cells/μL; P=0.002). Conclusions Oral SBI may decrease inflammation and warrants further exploration as a potential strategy to improve gut integrity and decrease systemic inflammation among persons receiving prolonged suppressive ART.
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Affiliation(s)
- Netanya S Utay
- Department of Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas
| | - Anoma Somasunderam
- Department of Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas
| | | | - Bryon W Petschow
- Entera Health, Inc., currently located at 2425 Oak Tree Ct., Ankeny, Iowa
| | | | - Ma Somsouk
- Department of Medicine, University of California, San Francisco, San Francisco, California
| | | | - Eric M Weaver
- Entera Health, Inc., currently located at 2425 Oak Tree Ct., Ankeny, Iowa
| | - Audrey L Shaw
- Entera Health, Inc., currently located at 2425 Oak Tree Ct., Ankeny, Iowa
| | - David M Asmuth
- Department of Medicine, University of California Davis Medical Center, Sacramento, California
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28
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Ramendra R, Isnard S, Mehraj V, Chen J, Zhang Y, Finkelman M, Routy JP. Circulating LPS and (1→3)-β-D-Glucan: A Folie à Deux Contributing to HIV-Associated Immune Activation. Front Immunol 2019; 10:465. [PMID: 30967860 PMCID: PMC6430738 DOI: 10.3389/fimmu.2019.00465] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 02/21/2019] [Indexed: 12/12/2022] Open
Abstract
Immune activation is the driving force behind the occurrence of AIDS and non-AIDS events, and is only partially reduced by antiretroviral therapy (ART). Soon after HIV infection, intestinal CD4+ T cells are depleted leading to epithelial gut damage and subsequent translocation of microbes and/or their products into systemic circulation. Bacteria and fungi are the two most abundant populations of the gut microbiome. Circulating lipopolysaccharide (LPS) and (1→3)-β-D-Glucan (βDG), major components of bacterial and fungal cell walls respectively, are measured as markers of microbial translocation in the context of compromised gut barriers. While LPS is a well-known inducer of innate immune activation, βDG is emerging as a significant source of monocyte and NK cell activation that contributes to immune dysfunction. Herein, we critically evaluated recent literature to untangle the respective roles of LPS and βDG in HIV-associated immune dysfunction. Furthermore, we appraised the relevance of LPS and βDG as biomarkers of disease progression and immune activation on ART. Understanding the consequences of elevated LPS and βDG on immune activation will provide insight into novel therapeutic strategies against the occurrence of AIDS and non-AIDS events.
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Affiliation(s)
- Rayoun Ramendra
- Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada.,Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montreal, QC, Canada.,Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
| | - Stéphane Isnard
- Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada.,Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montreal, QC, Canada
| | - Vikram Mehraj
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada
| | - Jun Chen
- Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada.,Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montreal, QC, Canada
| | - Yonglong Zhang
- Associates of Cape Cod Inc., Falmouth, MA, United States
| | | | - Jean-Pierre Routy
- Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada.,Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montreal, QC, Canada.,Division of Hematology, McGill University Health Centre, Montreal, QC, Canada
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29
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Microbial translocation revisited: targeting the endotoxic potential of gut microbes in HIV-infected individuals. AIDS 2019; 33:645-653. [PMID: 30531315 DOI: 10.1097/qad.0000000000002087] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Translocation of microbial products such as lipopolysaccharides (LPS) from the gut may contribute to chronic inflammation in HIV-infected individuals. Recent studies indicate that differences in degree of acylation of gut-bacterial-derived LPS may explain variable immune effects, with hexa-acylated rather than penta-acylated LPS having proinflammatory capacity. We investigated whether the degree of acylation of gut-derived LPS associates with systemic inflammation, and the potential effect of probiotic intervention. METHODS Gut microbiota profiles from a probiotics intervention were investigated and validated in a cohort of HIV-infected individuals commencing antiretroviral therapy. The PiCRUSt software was used to predict overall functional capacity of the microbiota and in-house bioinformatics to distinguish between bacteria producing hexa-acylated and penta-acylated LPS. RESULTS AND CONCLUSION HIV-infected individuals with the highest ratio of proinflammatory hexa-acylated LPS to noninflammatory penta-acylated LPS-producing bacteria exhibited increased levels of systemic inflammation (neopterin, P < 0.001) and tryptophan catabolism (kynurenine/tryptophan ratio, P = 0.01), indicating a link between proinflammatory LPS, tryptophan catabolism and inflammation. After probiotics for 8 weeks, there was a decrease in Gram-negative bacteria (P = 0.01), related primarily to a reduction in bacteria producing penta-acylated LPS (P = 0.01), but not hexa-acylated LPS. The reduction in Gram-negative bacteria correlated positively with decreased plasma LPS (r = 0.72), mainly related to a reduction in bacteria producing noninflammatory penta-acylated LPS (r = 0.58). Notably, gut bacteria producing hexa-acylated LPS were outnumbered by penta-acylated LPS with a factor of 25 in HIV-infected individuals. Further studies are warranted to determine whether microbes producing hexa-acylated LPS might be a more relevant trigger of systemic inflammation compared with plasma LPS captured by the existing limulus assay.
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Immune Activation, Inflammation, and Non-AIDS Co-Morbidities in HIV-Infected Patients under Long-Term ART. Viruses 2019; 11:v11030200. [PMID: 30818749 PMCID: PMC6466530 DOI: 10.3390/v11030200] [Citation(s) in RCA: 300] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 02/19/2019] [Accepted: 02/26/2019] [Indexed: 02/07/2023] Open
Abstract
Despite effective antiretroviral therapy (ART), people living with HIV (PLWH) still present persistent chronic immune activation and inflammation. This condition is the result of several factors including thymic dysfunction, persistent antigen stimulation due to low residual viremia, microbial translocation and dysbiosis, caused by the disruption of the gut mucosa, co-infections, and cumulative ART toxicity. All of these factors can create a vicious cycle that does not allow the full control of immune activation and inflammation, leading to an increased risk of developing non-AIDS co-morbidities such as metabolic syndrome and cardiovascular diseases. This review aims to provide an overview of the most recent data about HIV-associated inflammation and chronic immune exhaustion in PLWH under effective ART. Furthermore, we discuss new therapy approaches that are currently being tested to reduce the risk of developing inflammation, ART toxicity, and non-AIDS co-morbidities.
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Fitzgerald FC, Lhomme E, Harris K, Kenny J, Doyle R, Kityo C, Shaw LP, Abongomera G, Musiime V, Cook A, Brown JR, Brooks A, Owen-Powell E, Gibb DM, Prendergast AJ, Sarah Walker A, Thiebaut R, Klein N. Microbial Translocation Does Not Drive Immune Activation in Ugandan Children Infected With HIV. J Infect Dis 2019; 219:89-100. [PMID: 30107546 PMCID: PMC6284549 DOI: 10.1093/infdis/jiy495] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 08/10/2018] [Indexed: 12/12/2022] Open
Abstract
Objective Immune activation is associated with morbidity and mortality during human immunodeficiency virus (HIV) infection, despite receipt of antiretroviral therapy (ART). We investigated whether microbial translocation drives immune activation in HIV-infected Ugandan children. Methods Nineteen markers of immune activation and inflammation were measured over 96 weeks in HIV-infected Ugandan children in the CHAPAS-3 Trial and HIV-uninfected age-matched controls. Microbial translocation was assessed using molecular techniques, including next-generation sequencing. Results Of 249 children included, 142 were infected with HIV; of these, 120 were ART naive, with a median age of 2.8 years (interquartile range [IQR], 1.7-4.0 years) and a median baseline CD4+ T-cell percentage of 20% (IQR, 14%-24%), and 22 were ART experienced, with a median age of 6.5 years (IQR, 5.9-9.2 years) and a median baseline CD4+ T-cell percentage of 35% (IQR, 31%-39%). The control group comprised 107 children without HIV infection. The median increase in the CD4+ T-cell percentage was 17 percentage points (IQR, 12-22 percentage points) at week 96 among ART-naive children, and the viral load was <100 copies/mL in 76% of ART-naive children and 91% of ART-experienced children. Immune activation decreased with ART use. Children could be divided on the basis of immune activation markers into the following 3 clusters: in cluster 1, the majority of children were HIV uninfected; cluster 2 comprised a mix of HIV-uninfected children and HIV-infected ART-naive or ART-experienced children; and in cluster 3, the majority were ART naive. Immune activation was low in cluster 1, decreased in cluster 3, and persisted in cluster 2. Blood microbial DNA levels were negative or very low across groups, with no difference between clusters except for Enterobacteriaceae organisms (the level was higher in cluster 1; P < .0001). Conclusion Immune activation decreased with ART use, with marker clustering indicating different activation patterns according to HIV and ART status. Levels of bacterial DNA in blood were low regardless of HIV status, ART status, and immune activation status. Microbial translocation did not drive immune activation in this setting. Clinical Trials Registration ISRCTN69078957.
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Affiliation(s)
| | - Edouard Lhomme
- INSERM, Bordeaux Population Health Research Centre, UMR 1219, University of Bordeaux, ISPED
- Statistics in System Biology and Translational Medicine (SISTM Team), INRIA Research Centre
- Vaccine Research Institute (VRI), Créteil, France
| | - Kathryn Harris
- Microbiology, Virology, and Infection Prevention and Control, Camelia Botnar Laboratories, GOS National Health Service Foundation Trust
| | - Julia Kenny
- Infection, Immunity, and Inflammation Programme
| | - Ronan Doyle
- Microbiology, Virology, and Infection Prevention and Control, Camelia Botnar Laboratories, GOS National Health Service Foundation Trust
| | | | - Liam P Shaw
- Infection, Immunity, and Inflammation Programme
| | | | | | - Adrian Cook
- Medical Research Council Clinical Trials Unit at UCL
| | - Julianne R Brown
- Microbiology, Virology, and Infection Prevention and Control, Camelia Botnar Laboratories, GOS National Health Service Foundation Trust
| | - Anthony Brooks
- University College London (UCL) Genomics, UCL Great Ormond Street (GOS) Institute of Child Health
| | | | - Diana M Gibb
- Medical Research Council Clinical Trials Unit at UCL
| | - Andrew J Prendergast
- Blizard Institute, Queen Mary University of London, London, United Kingdom
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | | | - Rodolphe Thiebaut
- INSERM, Bordeaux Population Health Research Centre, UMR 1219, University of Bordeaux, ISPED
- Statistics in System Biology and Translational Medicine (SISTM Team), INRIA Research Centre
- Vaccine Research Institute (VRI), Créteil, France
| | - Nigel Klein
- Infection, Immunity, and Inflammation Programme
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Mechanisms of Cardiovascular Disease in the Setting of HIV Infection. Can J Cardiol 2018; 35:238-248. [PMID: 30825947 DOI: 10.1016/j.cjca.2018.12.024] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 12/11/2018] [Accepted: 12/11/2018] [Indexed: 12/12/2022] Open
Abstract
Although the initial reports of increased cardiovascular (CV) disease in the setting of advanced AIDS were reported approximately 30 years ago, advances in antiretroviral therapy and immediate initiation of therapy on diagnosis have transformed what was once a deadly infectious disease into a chronic health condition. Accordingly, the types of CV diseases occurring in HIV have shifted from pericardial effusions and dilated cardiomyopathy to atherosclerosis and heart failure. The underlying pathophysiology of HIV-associated CV disease remains poorly understood, partly because of the rapidly evolving nature of HIV treatment and because clinical endpoints take many years to develop. The gut plays an important role in the early pathogenesis of HIV infection as HIV preferentially infects CD4+ T cells, 80% of which are located in gut mucosa. The loss of these T cells damages gut mucosa resulting in increased gut permeability and microbial translocation, which incites chronic inflammation and immune activation. Antiretroviral therapy does not cure HIV infection and immune abnormalities persist. These abnormalities correlate with mortality and CV events. The effects of antiretroviral therapy on CV risk are complex; treatment reduces inflammation and other markers of CV risk but induces lipid abnormalities, most commonly hypertriglyceridemia. On a molecular level, monocytes/macrophages, platelet reactivity, and immune cell activation, which play a role in the general population, may be heightened in the setting of HIV and contribute to HIV-associated atherosclerosis. Chronic inflammation represents an inviting therapeutic target in HIV, as it does in uninfected persons with atherosclerosis.
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Rajasuriar R, Hearps AC, Crowe SM, Anzinger JJ, Palmer CS. Suppression of monocyte inflammatory and coagulopathy responses in HIV infection. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:277. [PMID: 30094263 DOI: 10.21037/atm.2018.06.20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Reena Rajasuriar
- Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.,Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, Malaysia.,Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
| | - Anna C Hearps
- Life Sciences, Burnet Institute, Melbourne, VIC, Australia.,Department of Infectious Diseases, Monash University, Melbourne, VIC, Australia
| | - Suzanne M Crowe
- Life Sciences, Burnet Institute, Melbourne, VIC, Australia.,School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Joshua J Anzinger
- Department of Microbiology, University of the West Indies, Mona, Kingston, Jamaica
| | - Clovis S Palmer
- Life Sciences, Burnet Institute, Melbourne, VIC, Australia.,School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.,Department of Microbiology and Immunology, University of Melbourne, Melbourne, VIC, Australia
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Wilson QN, Wells M, Davis AT, Sherrill C, Tsilimigras MCB, Jones RB, Fodor AA, Kavanagh K. Greater Microbial Translocation and Vulnerability to Metabolic Disease in Healthy Aged Female Monkeys. Sci Rep 2018; 8:11373. [PMID: 30054517 PMCID: PMC6063974 DOI: 10.1038/s41598-018-29473-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 07/06/2018] [Indexed: 12/14/2022] Open
Abstract
Monkeys demonstrate gastrointestinal barrier dysfunction (leaky gut) as evidenced by higher biomarkers of microbial translocation (MT) and inflammation with ageing despite equivalent health status, and lifelong diet and environmental conditions. We evaluated colonic structural, microbiomic and functional changes in old female vervet monkeys (Chlorocebus aethiops sabeus) and how age-related leaky gut alters responses to Western diet. We additionally assessed serum bovine immunoglobulin therapy to lower MT burden. MT was increased in old monkeys despite comparable histological appearance of the ascending colon. Microbiome profiles from 16S sequencing did not show large differences by age grouping, but there was evidence for higher mucosal bacterial loads using qPCR. Innate immune responses were increased in old monkeys consistent with higher MT burdens. Western diet challenge led to elevations in glycemic and hepatic biochemistry values only in old monkeys, and immunoglobulin therapy was not effective in reducing MT markers or improving metabolic health. We interpret these findings to suggest that ageing may lead to lower control over colonization at the mucosal surface, and reduced clearance of pathogens resulting in MT and inflammation. Leaky gut in ageing, which is not readily rescued by innate immune support with immunoglobulin, primes the liver for negative consequences of high fat, high sugar diets.
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Affiliation(s)
- Quentin N Wilson
- Wake Forest School of Medicine, Department of Pathology, Winston-Salem, USA
| | - Magan Wells
- Wake Forest School of Medicine, Department of Pathology, Winston-Salem, USA
| | - Ashley T Davis
- Wake Forest School of Medicine, Department of Pathology, Winston-Salem, USA
| | - Christina Sherrill
- Wake Forest School of Medicine, Department of Pathology, Winston-Salem, USA
| | - Matthew C B Tsilimigras
- University of North Carolina at Charlotte, Department of Bioinformatics and Genomics, Charlotte, USA
| | - Roshonda B Jones
- University of North Carolina at Charlotte, Department of Bioinformatics and Genomics, Charlotte, USA
| | - Anthony A Fodor
- University of North Carolina at Charlotte, Department of Bioinformatics and Genomics, Charlotte, USA
| | - Kylie Kavanagh
- Wake Forest School of Medicine, Department of Pathology, Winston-Salem, USA.
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Altered gut microbiome composition in HIV infection: causes, effects and potential intervention. Curr Opin HIV AIDS 2018; 13:73-80. [PMID: 29045252 DOI: 10.1097/coh.0000000000000429] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW Aim of this review is to summarize the alterations occurring in gut microbiome composition after HIV infection, and to underline how intestinal dysbiosis can affect immune homeostasis, immune recovery, and persisting immune activation under antiretroviral therapy (ART). Many interventions have been suggested, mostly with inconclusive results. RECENT FINDINGS Recent evidence showed that gut microbiota from HIV-infected patients harbor reproducible differences compared to uninfected individuals. In this line, there is growing evidence that alterations in gut ecology during HIV infection correlate with persistence of immune defects and chronic inflammation. A reduced microbial diversity in feces of HIV-infected patients is highly associated with microbial translocation and monocyte activation markers; moreover, changes in mucosa-associated bacteria correlate with inflammation and T-cell activation. SUMMARY Studying the human host-microbiota interaction suggests that the consequences of HIV infection on microbial composition can influence immune status in HIV patients. ART induces microbiome changes that are independent of HIV infection, and some imply that ART may enhance dysbiosis. Studies and trials evaluated the effects of administering probiotics and prebiotics, finding a potential benefit on inflammation markers and immune cell activation. Emerging data on fecal microbial transplantation need to be assessed with further studies.
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Abstract
PURPOSE OF REVIEW The article describes recent advances in understanding the causes and consequences of microbial translocation in HIV and simian immunodeficiency virus infections. RECENT FINDINGS Persistent microbial translocation contributes to aberrant immune activation in immunodeficiency lentiviral infections and thereby, pathogenesis and mortality. Efforts to delineate the circumstances surrounding translocation have benefited from use of simian immunodeficiency virus-infected nonhuman primates and highlight the overwhelming immunologic diversion caused by translocating microbes. The use of therapeutics aimed at reducing microbial translocation show promise and will benefit from continued research into the mechanisms that promote systemic microbial dissemination in treated and untreated infections. SUMMARY Insights into the source and identity of translocating microbes in lentiviral infections continue to enhance the development of adjunct therapeutics.
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Tian RR, Zhang MX, Zhang LT, Zhang P, Ma JP, Liu M, Devenport M, Zheng P, Zhang XL, Lian XD, Ye M, Zheng HY, Pang W, Zhang GH, Zhang LG, Liu Y, Zheng YT. CD24 and Fc fusion protein protects SIVmac239-infected Chinese rhesus macaque against progression to AIDS. Antiviral Res 2018; 157:9-17. [PMID: 29983395 DOI: 10.1016/j.antiviral.2018.07.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 06/28/2018] [Accepted: 07/02/2018] [Indexed: 01/25/2023]
Abstract
Chronic immune activation and systemic inflammation are underlying causes of acquired immunodeficiency syndrome (AIDS). Products of virus replication and microbial translocation, co-infection or opportunistic pathogens, and danger-associated molecular patterns have been reported to contribute to chronic immune activation and inflammation in human immunodeficiency virus type-1/simian immunodeficiency virus (HIV-1/SIV) infection or other disease. To develop new strategies and therapies for HIV-1/AIDS, we tested if the CD24 and Fc fusion protein (CD24Fc), which interacts with danger-associated molecular patterns and sialic acid binding Ig-like lectin to attenuate inflammation, can protect Chinese rhesus macaques (ChRMs) with SIV infection. We found that CD24Fc treatment decreased weight loss, wasting syndrome, intractable diarrhea, and AIDS morbidity and mortality, while it was well tolerated by SIV-infected animals. Corresponding to the elimination of intractable diarrhea, CD24Fc significantly reduced the expression of IL-6 and indoleamine 2, 3-dioxygenase-1 in peripheral blood mononuclear cell and inflammation in the ileum, colon and rectum based on the reduction of inflammatory cells, pathological scores and expression of inflammatory cytokines. Furthermore, although CD24Fc did not restore CD4+ T cell number or significantly change T cell subsets or CD4+ T cell activation, it maintained low levels of plasma soluble CD14, CD8+ T cell activation, viral load and proviral load in the peripheral blood mononuclear cells and marrow. These results suggested that CD24Fc confers protection to SIV-infected ChRMs against progression to AIDS. It was also implied that CD24Fc may be a potential therapeutic approach for the control of HIV-1/AIDS.
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Affiliation(s)
- Ren-Rong Tian
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
| | - Ming-Xu Zhang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China
| | - Lin-Tao Zhang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
| | - Peng Zhang
- Center for Cancer and Immunology Research and Division of Pathology, Children's Research Institute, Children's National Medical Center, Washington DC 20010, USA
| | - Jian-Ping Ma
- CAS Key Laboratory for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Mingyue Liu
- Center for Cancer and Immunology Research and Division of Pathology, Children's Research Institute, Children's National Medical Center, Washington DC 20010, USA
| | | | - Pan Zheng
- Center for Cancer and Immunology Research and Division of Pathology, Children's Research Institute, Children's National Medical Center, Washington DC 20010, USA; OncoImmune, Inc., Rockville, MD, USA
| | - Xiao-Liang Zhang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
| | - Xiao-Dong Lian
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China
| | - Mei Ye
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China
| | - Hong-Yi Zheng
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
| | - Wei Pang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
| | - Gao-Hong Zhang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
| | - Li-Guo Zhang
- CAS Key Laboratory for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
| | - Yang Liu
- Center for Cancer and Immunology Research and Division of Pathology, Children's Research Institute, Children's National Medical Center, Washington DC 20010, USA; OncoImmune, Inc., Rockville, MD, USA.
| | - Yong-Tang Zheng
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China; The National Kunming High Level Biosafety Research Center for Nonhuman Primate, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
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Ploquin MJ, Casrouge A, Madec Y, Noël N, Jacquelin B, Huot N, Duffy D, Jochems SP, Micci L, Lécuroux C, Boufassa F, Booiman T, Garcia‐Tellez T, Ghislain M, Grand RL, Lambotte O, Kootstra N, Meyer L, Goujard C, Paiardini M, Albert ML, Müller‐Trutwin M. Systemic DPP4 activity is reduced during primary HIV-1 infection and is associated with intestinal RORC + CD4 + cell levels: a surrogate marker candidate of HIV-induced intestinal damage. J Int AIDS Soc 2018; 21:e25144. [PMID: 29987877 PMCID: PMC6038000 DOI: 10.1002/jia2.25144] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 05/22/2018] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION Combined anti-retroviral therapy (cART) transformed HIV-1 from a deadly disease into a chronic infection, but does not cure HIV infection. It also does not fully restore HIV-induced gut damage unless administered extremely early after infection. Additional biomarkers are needed to evaluate the capacity of therapies aimed at HIV remission/cure to restore HIV-induced intestinal immune damage and limit chronic inflammation. Herein, we aimed to identify a systemic surrogate marker whose levels would reflect gut immune damage such as intestinal Th17 cell loss starting from primary HIV-1 infection. METHODS Biomarker discovery approaches were performed in four independent cohorts, covering HIV-1 primary and chronic infection in 496 naïve or cART-treated patients (Amsterdam cohort (ACS), ANRS PRIMO, COPANA and CODEX cohorts). The concentration and activity of soluble Dipeptidylpeptidase 4 (sDPP4) were quantified in the blood from these patients, including pre- and post-infection samples in the ACS cohort. For quantification of DPP4 in the gut, we utilized two non-human primate models, representing pathogenic (macaque) and non-pathogenic (African green monkey) SIV infection. Four gut compartments were analysed in each animal model (ileum, jejunum, colon and rectum) for quantification of DPP4, RORC and TBX21 gene expression in sorted CD4+ cells. To analyse if sDPP4 levels increase when Th17 cells were restored, we quantified sDPP4 in plasma from SIV-infected macaques treated with IL-21. RESULTS We showed that sDPP4 levels were strongly decreased in primary HIV-1 infection. Strikingly, sDPP4 levels in primary HIV-1 infection predicted time to AIDS. They were not increased by cART in chronic HIV-1 infection (median 36 months on cART). In the gut of SIV-infected non-human primates, DPP4 mRNA was higher in CD4+ than CD4- leucocytes. DPP4 specifically correlated with RORC expression, a Th17 marker, in CD4+ cells from the intestine. We further demonstrated that sDPP4 activity levels were increased in animals treated with IL-21 and that this increase was associated with restoration of the Th17 compartment and reduced inflammation. Furthermore, DPP4 mRNA levels in small intestine CD4+ cells positively correlated with circulating DPP4 activity. CONCLUSION These data provide evidence that blood sDPP4 levels could be useful as a correlate for HIV-induced intestinal damage.
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Affiliation(s)
| | - Armanda Casrouge
- Institut PasteurUnité Immunobiologie des cellules dendritiquesParisFrance
- INSERM U1223ParisFrance
| | - Yoann Madec
- Institut PasteurURE Epidémiologie des Maladies EmergentesParisFrance
| | - Nicolas Noël
- Institut PasteurUnité HIVInflammation et PersistanceParisFrance
- Assistance Publique – Hôpitaux de ParisService de Médecine Interne et Immunologie CliniqueGroupe Hospitalier Universitaire Paris Sud, Hôpital BicêtreLe Kremlin‐BicêtreFrance
- IDMIT DepartmentCEAUniversité Paris SudInserm U1184Immunology of viral infections and auto‐immune diseases (IMVA)IBFJFontenay‐aux‐Roses and Kremlin‐BicêtreFrance
- Université Paris SudLe Kremlin BicêtreFrance
| | | | - Nicolas Huot
- Institut PasteurUnité HIVInflammation et PersistanceParisFrance
| | - Darragh Duffy
- Institut PasteurUnité Immunobiologie des cellules dendritiquesParisFrance
- INSERM U1223ParisFrance
| | - Simon P Jochems
- Institut PasteurUnité HIVInflammation et PersistanceParisFrance
- Present address:
Liverpool School of Tropical MedicineLiverpoolUK
| | - Luca Micci
- Emory University School of Medicine and Yerkes National Primate Research CenterAtlantaGeorgiaUSA
| | - Camille Lécuroux
- IDMIT DepartmentCEAUniversité Paris SudInserm U1184Immunology of viral infections and auto‐immune diseases (IMVA)IBFJFontenay‐aux‐Roses and Kremlin‐BicêtreFrance
| | | | - Thijs Booiman
- Academisch Medisch CentrumLaboratory of Viral Immune PathogenesisAmsterdamThe Netherlands
| | | | | | - Roger Le Grand
- IDMIT DepartmentCEAUniversité Paris SudInserm U1184Immunology of viral infections and auto‐immune diseases (IMVA)IBFJFontenay‐aux‐Roses and Kremlin‐BicêtreFrance
| | - Olivier Lambotte
- Assistance Publique – Hôpitaux de ParisService de Médecine Interne et Immunologie CliniqueGroupe Hospitalier Universitaire Paris Sud, Hôpital BicêtreLe Kremlin‐BicêtreFrance
- IDMIT DepartmentCEAUniversité Paris SudInserm U1184Immunology of viral infections and auto‐immune diseases (IMVA)IBFJFontenay‐aux‐Roses and Kremlin‐BicêtreFrance
- Université Paris SudLe Kremlin BicêtreFrance
| | - Neeltje Kootstra
- Academisch Medisch CentrumLaboratory of Viral Immune PathogenesisAmsterdamThe Netherlands
| | - Laurence Meyer
- Université Paris SudLe Kremlin BicêtreFrance
- INSERM CESP U1018Université Paris SudLe Kremlin‐BicêtreFrance
| | - Cecile Goujard
- Assistance Publique – Hôpitaux de ParisService de Médecine Interne et Immunologie CliniqueGroupe Hospitalier Universitaire Paris Sud, Hôpital BicêtreLe Kremlin‐BicêtreFrance
- Université Paris SudLe Kremlin BicêtreFrance
- INSERM CESP U1018Université Paris SudLe Kremlin‐BicêtreFrance
| | - Mirko Paiardini
- Emory University School of Medicine and Yerkes National Primate Research CenterAtlantaGeorgiaUSA
| | - Matthew L Albert
- Institut PasteurUnité Immunobiologie des cellules dendritiquesParisFrance
- Present address:
Department of Cancer ImmunologyGenentech Inc.San FranciscoCAUSA
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Dzingarski D, Mladenovska K. Pharmacotherapy in chronic kidney disease hyperphosphatemia – effects on vascular calcification and bone health. MAKEDONSKO FARMACEVTSKI BILTEN 2017. [DOI: 10.33320/maced.pharm.bull.2017.63.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Hyperphosphatemia (HP) in patients with chronic kidney disease (CKD) leads to complications such as renal osteodistrophy, cardiovascular calcification and hemodynamic abnormalities, all of them having a serious impact on the survival rate and quality of life. Also, HP is a key pathogenic factor in the development of secondary hyperparathyroidism (SHPT) in CKD. Having in regard the significance of controlling serum phosphorus levels (Pi), in this paper, the needs and obstacles to successful pharmacological management of HP in CKD are presented, with an overview of major classes of phosphate binders (PBs) and other drugs affecting Pi level, such as active vitamin D sterols and calcimimetics (CMs). In addition, their effects on progression of cardiovascular calcification and bone health are elaborated. In this regard, a PubMed search was carried out to capture all abstracts and articles relevant to the topic of CKD, HP and mineral metabolism, bone disorders and vascular/valvular calcification (VC), published from January 2007 to August 2017. The search was limited to English language, with the search terms including drug name AND hyperphosphatemia or cardiovascular calcification or bone disorder. Comparative studies, clinical studies/trials and meta-analyses related to different classes/representatives of PBs, vitamin D analogues and CMs were reviewed and research data related to their efficacy and safety compared.
Keywords: chronic kidney disease, hyperphosphatemia, phosphate binders, active vitamin D sterols, calcimimetics, bone disorders, cardiovascular calcification
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Affiliation(s)
- Dimce Dzingarski
- Faculty of Pharmacy, University “Ss Cyril and Methodius”, Mother Theresa St. 47, 1000 Skopje, Republic of Macedonia
| | - Kristina Mladenovska
- Faculty of Pharmacy, University “Ss Cyril and Methodius”, Mother Theresa St. 47, 1000 Skopje, Republic of Macedonia
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40
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Abstract
PURPOSE OF REVIEW This review focuses on the differential effects of contemporary antiretrovirals on systemic inflammation as heightened immune activation is linked to important co-morbidities and mortality with HIV infection. RECENT FINDINGS Antiretroviral therapy (ART) reduces dramatically systemic inflammation and immune activation, but not to levels synchronous with HIV-uninfected populations. In one ART initiation trial, integrase inhibitors appear to reduce inflammation to a greater degree than non-nucleoside reverse transcriptase inhibitors (NNRTIs); however, it is not clear that there are beneficial effects on inflammation resulting from treatment with integrase inhibitors compared to PIs, between PIs and NNRTIs, between specific nucleoside reverse transcriptase inhibitors, or with maraviroc in ART-naïve patients. In ART switch studies, changing to an integrase inhibitor from a PI-, NNRTI-, or enfuvirtide-containing regimen has resulted in improvement in several markers of inflammation. Additional research is needed to conclusively state whether there are clear differences in effects of specific antiretrovirals on inflammation and immune activation in HIV.
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Abstract
Infection with the human immunodeficiency virus (HIV), and subsequent treatment with antiretroviral therapy (ART), is often associated with perturbations in lipid profiles. Furthermore, persistent inflammation, in spite of suppression of viral replication by ART, likely contributes to modifications in lipid composition and function, exacerbating risk for development of cardiovascular disease (CVD). Increased levels of several pro-inflammatory lipid species, including oxidized low-density lipoprotein (LDL) and high-density lipoprotein (HDL), have been measured in HIV-infected persons and are associated with markers of immune activation. The mechanisms linked to this bidirectional relationship in which inflammation increases lipid levels and promotes their modification, and these modified lipid species perpetuate inflammatory processes, require further investigation. Treatment with statins and other lifestyle modifications, including improvement in dietary intake and exercise, are critical to reducing CVD risk. Well-designed clinical trials that take into account the complex relationships among lipids and inflammation within persons infected with HIV need to be considered.
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Affiliation(s)
- Nicholas T Funderburg
- School of Health and Rehabilitation Sciences, Division of Medical Laboratory Science, Ohio State University, 453 W. 10th Ave., 535A Atwell Hall, Columbus, OH, 43210, USA
| | - Nehal N Mehta
- Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, Bethesda, MD, 20892, USA.
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MicroRNAs: novel tools to block gut inflammation in HIV? AIDS 2017; 31:2017-2018. [PMID: 28857780 DOI: 10.1097/qad.0000000000001609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Sun Y, Fu Y, Zhang Z, Tang T, Liu J, Ding H, Han X, Xu J, Chu Z, Shang H, Jiang Y. The investigation of CD4+T-cell functions in primary HIV infection with antiretroviral therapy. Medicine (Baltimore) 2017; 96:e7430. [PMID: 28700479 PMCID: PMC5515751 DOI: 10.1097/md.0000000000007430] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Human immunodeficiency virus (HIV) infection leads to reduced CD4T-cell counts and immune dysfunction. Initiation of antiretroviral therapy (ART) in HIV primary infection has been recommended to achieve an optimal clinical outcome, but a comprehensive study on restoration of CD4T-cell function in primary HIV-infected individuals with ART still needs to be eluciated. We investigated longitudinal changes in the CD4T-cell counts, phenotypes, and functions in HIV-infected individuals with early ART (initiated within 6 months after HIV infection) or later ART (initiated more than 12 months after HIV infection). Patients from early ART and later ART groups had received ART for at least 1 year. Individuals with early ART had more CD4T cells, a faster rate of CD4T-cell recovery than those receiving later ART; the levels of CD4T-cell activation and senescence were lower in early ART compared to those with later ART (P = .031; P = .016), but the activation was higher than normal controls (NC) (P = .001); thymic emigrant function was more upregulated in early ART than in later ART (P = .015), but still lower than NC (P = .027); proliferative capacity and interferon-γ secretion of CD4T cells were significantly decreased in primary infection (P < .001; P = .029), and early ART restored these CD4T-cell functions, there is no difference with NC, later ART could partially restore the functions of CD4T cells, but it remained lower than that of NC (P = .005; P = .019). Early ART could better improve CD4T-cell function.
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44
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Mudd JC, Brenchley JM. Gut Mucosal Barrier Dysfunction, Microbial Dysbiosis, and Their Role in HIV-1 Disease Progression. J Infect Dis 2017; 214 Suppl 2:S58-66. [PMID: 27625432 DOI: 10.1093/infdis/jiw258] [Citation(s) in RCA: 129] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Distinct pathological events occur within the gastrointestinal (GI) tract of Asian macaques with progressive simian immunodeficiency virus (SIV) infection and humans with human immunodeficiency virus type 1 (HIV-1) infection that are critical in shaping disease course. These events include depletion and functional alteration of GI-resident CD4(+) T cells, loss of antigen-presenting cells, loss of innate lymphocytes, and possible alterations to the composition of the gut microbiota. These contribute to structural damage to the GI tract and systemic translocation of GI tract microbial products. These translocated microbial products directly stimulate the immune system, and there is now overwhelming evidence that this drives chronic immune activation in HIV-1 and SIV infection. While combined antiretroviral therapy (cART) in HIV-1-infected subjects generally allows for immune reconstitution in peripheral blood, reconstitution of the GI tract occurs at a much slower pace, and both immunological and structural abnormalities persist in the GI tract. Importantly, studies of large cohorts of individuals have linked suboptimal GI reconstitution to residual inflammation and heightened morbidities in HIV-1-infected cART recipients. As a result, current era treatments aimed at augmenting restoration of the GI tract hold promise in returning cART recipients to full health.
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Affiliation(s)
- Joseph C Mudd
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Jason M Brenchley
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
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Villar-García J, Güerri-Fernández R, Moya A, González A, Hernández JJ, Lerma E, Guelar A, Sorli L, Horcajada JP, Artacho A, D´Auria G, Knobel H. Impact of probiotic Saccharomyces boulardii on the gut microbiome composition in HIV-treated patients: A double-blind, randomised, placebo-controlled trial. PLoS One 2017; 12:e0173802. [PMID: 28388647 PMCID: PMC5384743 DOI: 10.1371/journal.pone.0173802] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 02/22/2017] [Indexed: 02/07/2023] Open
Abstract
Dysbalance in gut microbiota has been linked to increased microbial translocation, leading to chronic inflammation in HIV-patients, even under effective HAART. Moreover, microbial translocation is associated with insufficient reconstitution of CD4+T cells, and contributes to the pathogenesis of immunologic non-response. In a double-blind, randomised, placebo-controlled trial, we recently showed that, compared to placebo, 12 weeks treatment with probiotic Saccharomyces boulardii significantly reduced plasma levels of bacterial translocation (Lipopolysaccharide-binding protein or LBP) and systemic inflammation (IL-6) in 44 HIV virologically suppressed patients, half of whom (n = 22) had immunologic non-response to antiretroviral therapy (<270 CD4+Tcells/μL despite long-term suppressed viral load). The aim of the present study was to investigate if this beneficial effect of the probiotic Saccharomyces boulardii is due to modified gut microbiome composition, with a decrease of some species associated with higher systemic levels of microbial translocation and inflammation. In this study, we used 16S rDNA gene amplification and parallel sequencing to analyze the probiotic impact on the composition of the gut microbiome (faecal samples) in these 44 patients randomized to receive oral supplementation with probiotic or placebo for 12 weeks. Compared to the placebo group, in individuals treated with probiotic we observed lower concentrations of some gut species, such as those of the Clostridiaceae family, which were correlated with systemic levels of bacterial translocation and inflammation markers. In a sub-study of these patients, we observed significantly higher parameters of microbial translocation (LBP, soluble CD14) and systemic inflammation in immunologic non-responders than in immunologic responders, which was correlated with a relative abundance of specific gut bacterial groups (Lachnospiraceae genus and Proteobacteria). Thus, in this work, we propose a new therapeutic strategy using the probiotic yeast S. boulardii to modify gut microbiome composition. Identifying pro-inflammatory species in the gut microbiome could also be a useful new marker of poor immune response and a new therapeutic target.
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Affiliation(s)
- Judit Villar-García
- Department of Infectious Diseases, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute, Institut Hospital del Mar d'Investigacions Mediques), Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Spain
- * E-mail:
| | - Robert Güerri-Fernández
- Department of Infectious Diseases, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute, Institut Hospital del Mar d'Investigacions Mediques), Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Spain
| | - Andrés Moya
- Joint Unit of Research in Genomics and Health, Foundation for the Promotion of Health and Biomedical Research in the Valencian Community (FISABIO) and Cavanilles Institute of Biodiversity and Evolutionary Biology (Universitat de València), València, Spain
- CIBER en Epidemiología y Salud Pública, Madrid, Spain
| | - Alicia González
- Department of Infectious Diseases, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute, Institut Hospital del Mar d'Investigacions Mediques), Barcelona, Spain
| | | | - Elisabet Lerma
- Department of Infectious Diseases, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute, Institut Hospital del Mar d'Investigacions Mediques), Barcelona, Spain
| | - Ana Guelar
- Department of Infectious Diseases, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute, Institut Hospital del Mar d'Investigacions Mediques), Barcelona, Spain
| | - Luisa Sorli
- Department of Infectious Diseases, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute, Institut Hospital del Mar d'Investigacions Mediques), Barcelona, Spain
| | - Juan P. Horcajada
- Department of Infectious Diseases, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute, Institut Hospital del Mar d'Investigacions Mediques), Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Spain
| | - Alejandro Artacho
- Joint Unit of Research in Genomics and Health, Foundation for the Promotion of Health and Biomedical Research in the Valencian Community (FISABIO) and Cavanilles Institute of Biodiversity and Evolutionary Biology (Universitat de València), València, Spain
| | - Giuseppe D´Auria
- Joint Unit of Research in Genomics and Health, Foundation for the Promotion of Health and Biomedical Research in the Valencian Community (FISABIO) and Cavanilles Institute of Biodiversity and Evolutionary Biology (Universitat de València), València, Spain
- CIBER en Epidemiología y Salud Pública, Madrid, Spain
| | - Hernando Knobel
- Department of Infectious Diseases, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute, Institut Hospital del Mar d'Investigacions Mediques), Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Spain
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Vachiat A, McCutcheon K, Tsabedze N, Zachariah D, Manga P. HIV and Ischemic Heart Disease. J Am Coll Cardiol 2017; 69:73-82. [DOI: 10.1016/j.jacc.2016.09.979] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 08/25/2016] [Accepted: 09/20/2016] [Indexed: 10/20/2022]
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Merlini E, Tincati C, Biasin M, Saulle I, Cazzaniga FA, d'Arminio Monforte A, Cappione AJ, Snyder-Cappione J, Clerici M, Marchetti GC. Stimulation of PBMC and Monocyte-Derived Macrophages via Toll-Like Receptor Activates Innate Immune Pathways in HIV-Infected Patients on Virally Suppressive Combination Antiretroviral Therapy. Front Immunol 2016; 7:614. [PMID: 28066424 PMCID: PMC5165253 DOI: 10.3389/fimmu.2016.00614] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 12/05/2016] [Indexed: 12/25/2022] Open
Abstract
In HIV-infected, combination antiretroviral therapy (cART)-treated patients, immune activation and microbial translocation persist and associate with inadequate CD4 recovery and morbidity/mortality. We analyzed whether alterations in the toll-like receptor (TLR) pathway could be responsible for the immune hyperactivation seen in these patients. PBMC/monocyte-derived macrophages (MDMs) of 28 HIV+ untreated and 35 cART-treated patients with HIV-RNA < 40 cp/mL [20 Full Responders (FRs): CD4 ≥ 350; 15 Immunological Non-Responders (INRs): CD4 < 350], as well as of 16 healthy controls were stimulated with a panel of TLR agonists. We measured: CD4/CD8/CD14/CD38/HLA-DR/Ki67/AnnexinV/CD69/TLR4/8 (Flow Cytometry); PBMC expression of 84 TLR pathway genes (qPCR); PBMC/MDM cytokine release (Multiplex); and plasma lipopolysaccharide (LPS)/sCD14 (LAL/ELISA). PBMC/MDM from cART patients responded weakly to LPS stimulation but released high amounts of pro-inflammatory cytokines. MDM from these patients were characterized by a reduced expression of HLA-DR+ MDM and failed to expand activated HLA-DR+ CD38+ T-lymphocytes. PBMC/MDM from cART patients responded more robustly to ssRNA stimulation; this resulted in a significant expansion of activated CD38 + CD8 and the release of amounts of pro-inflammatory cytokines comparable to those seen in untreated viremic patients. Despite greater constitutive TLR pathway gene expression, PBMC from INRs seemed to upregulate only type I IFN genes following TLR stimulation, whereas PBMC from full responders showed a broader response. Systemic exposure to microbial antigens drives immune activation during cART by triggering TLRs. Bacterial stimulation modifies MDM function/pro-inflammatory profile in cART patients without affecting T-lymphocytes; this suggests translocating bacteria as selective stimulus to chronic innate activation during cART. High constitutive TLR activation is seen in patients lacking CD4 recovery, suggesting an exhausted immune milieu, anergic to further antigen encounters.
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Affiliation(s)
- Esther Merlini
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan , Milan , Italy
| | - Camilla Tincati
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan , Milan , Italy
| | - Mara Biasin
- Department of Biomedical and Clinical Sciences - "L. Sacco", University of Milan , Milan , Italy
| | - Irma Saulle
- Department of Biomedical and Clinical Sciences - "L. Sacco", University of Milan , Milan , Italy
| | - Federico Angelo Cazzaniga
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan , Milan , Italy
| | - Antonella d'Arminio Monforte
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan , Milan , Italy
| | | | | | - Mario Clerici
- Department of Physiopathology and Transplants, University of Milan, Milan, Italy; Don C. Gnocchi Foundation, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
| | - Giulia Carla Marchetti
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan , Milan , Italy
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Serious Non-AIDS Events: Therapeutic Targets of Immune Activation and Chronic Inflammation in HIV Infection. Drugs 2016; 76:533-49. [PMID: 26915027 DOI: 10.1007/s40265-016-0546-7] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In the antiretroviral therapy (ART) era, serious non-AIDS events (SNAEs) have become the major causes of morbidity and mortality in HIV-infected persons. Early ART initiation has the strongest evidence for reducing SNAEs and mortality. Biomarkers of immune activation, inflammation and coagulopathy do not fully normalize despite virologic suppression and persistent immune activation is an important contributor to SNAEs. A number of strategies aimed to reduce persistent immune activation including ART intensification to reduce residual viremia; treatment of co-infections to reduce chronic antigen stimulation; the use of anti-inflammatory agents, reducing microbial translocation as well as interventions to improve immune recovery through cytokine administration and reducing lymphoid tissue fibrosis, have been investigated. To date, there is little conclusive evidence on which strategies beyond treatment of hepatitis B and C co-infections and reducing cardiovascular risk factors will result in clinical benefits in patients already on ART with viral suppression. The use of statins seems to show early promise and larger clinical trials are underway to confirm their efficacy. At this stage, clinical care of HIV-infected patients should therefore focus on early diagnosis and prompt ART initiation, treatment of active co-infections and the aggressive management of co-morbidities until further data are available.
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49
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Bandera A, Colella E, Rizzardini G, Gori A, Clerici M. Strategies to limit immune-activation in HIV patients. Expert Rev Anti Infect Ther 2016; 15:43-54. [PMID: 27762148 DOI: 10.1080/14787210.2017.1250624] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Antiretroviral treatment of HIV infection reduces, but does not eliminate, viral replication and down modulates immune activation. The persistence of low level HIV replication in the host, nevertheless, drives a smouldering degree of immune activation that is observed throughout the natural history of disease and is the main driving force sustaining morbidity and mortality. Areas covered: Early start of antiretroviral therapy (ART) and intensive management of behavioural risk factors are possible but, at best, marginally successful ways to manage immune activation. We review alternative, possible strategies to reduce immune activation in HIV infection including timing of ART initiation and ART intensification to reduce HIV residual viremia; switch of ART to newer molecules with reduced toxicity; use of anti inflammatory/immunomodulatory agents and, finally, interventions aimed at modifying the composition of the microbiota. Expert commentary: Current therapeutic strategies to limit immune activation are only marginally successful. Because HIV eradication is currently impossible, intensive studies are needed to determine if and how immune activation can be silenced in HIV infection.
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Affiliation(s)
- Alessandra Bandera
- a Clinic of Infectious Diseases, 'San Gerardo' Hospital - ASST Monza, School of Medicine and Surgery , University Milano-Bicocca , Monza , Italy
| | - Elisa Colella
- a Clinic of Infectious Diseases, 'San Gerardo' Hospital - ASST Monza, School of Medicine and Surgery , University Milano-Bicocca , Monza , Italy
| | - Giuliano Rizzardini
- b Department of Infectious Diseases , ASST Fatebenefratelli Sacco , Milano , Italy.,c School of Clinical Medicine, Faculty of Health Science , University of the Witwatersrand , Johannesburg , South Africa
| | - Andrea Gori
- a Clinic of Infectious Diseases, 'San Gerardo' Hospital - ASST Monza, School of Medicine and Surgery , University Milano-Bicocca , Monza , Italy
| | - Mario Clerici
- d Department of Physiopathology and Transplants , University of Milano , Milano , Italy.,e Don C. Gnocchi Foundation , Istituto di Ricovero e Cura a Carattere Scientifico [IRCCS] , Milano , Italy
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50
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Abstract
PURPOSE OF REVIEW This article describes the mechanisms and consequences of both microbial translocation and microbial dysbiosis in HIV infection. RECENT FINDINGS Microbes in HIV are likely playing a large role in contributing to HIV pathogenesis, morbidities and mortality. Two major disruptions to microbial systems in HIV infection include microbial translocation and microbiome dysbiosis. Microbial translocation occurs when the bacteria (or bacterial products) that should be in the lumen of the intestine translocate across the tight epithelial barrier into systemic circulation, where they contribute to inflammation and pathogenesis. This is associated with poorer health outcomes in HIV-infected individuals. In addition, microbial populations in the gastrointestinal tract are also altered after HIV infection, resulting in microbiome dysbiosis, which further exacerbates microbial translocation, epithelial barrier disruption, inflammation and mucosal immune functioning. SUMMARY Altered microbial regulation in HIV infection can lead to poor health outcomes, and understanding the mechanisms underlying microbial dysbiosis and translocation may result in novel pathways for therapeutic interventions.
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