• Bacteremia
• COVID-19
• Colonization
• Herpesviridae
• ICU
• Lymphocytopenia
• Mortality

• AIDS - acquired immunodeficiency syndrome
• African green monkey (AGM) (Chlorocebus aethiops)
• HIV - human immunodeficiency virus
• immune activation
• inflammation
• microbiome
• mucosal immune barrier
• nonhuman primate (NHP)

• Animals
• Chlorocebus aethiops
• HIV Infections
• CD8-Positive T-Lymphocytes
• Macaca mulatta
• Simian Acquired Immunodeficiency Syndrome
• Simian Immunodeficiency Virus
• Inflammation

• R01 DK113919 NIDDK NIH HHS
• R01 DK119936 NIDDK NIH HHS
• R01 HL154862 NHLBI NIH HHS
• R01 HL117715 NHLBI NIH HHS
• R01 DK131476 NIDDK NIH HHS
• R01 AI119346 NIAID NIH HHS
• R01 HL123096 NHLBI NIH HHS
• R01 DK130481 NIDDK NIH HHS

• Autoantibody
• Autoimmunity
• Idiopathic CD4 lymphocytopenia
• Opportunistic infections

• AIDS
• CD4+ T cells
• human immunodeficiency virus
• immune activation (IA)
• inflammation
• microbial translocation
• simian immunodeficiency virus (SIV)

Idiopathic CD4 lymphocytopenia is a condition characterized by low CD4 counts. It is rare and most of the information about this illness comes from case reports. Presentation is usually in the 4th decade of life with opportunistic infections, autoimmune disease or neoplasia. The pathophysiology of this condition is not well understood. Management revolves around treatment of the presenting condition and close follow-up of these patients. This review presents a narrative summary of the current literature on idiopathic CD4 lymphocytopenia.

• CD4 T cell lymphocytopenia
• autoimmune disease
• neoplasia
• opportunistic infections

Microbial translocation is now viewed as a central event in the pathogenesis of chronic inflammation during HIV infection. Thymic function failure is another crucial factor involved in HIV disease progression. The goal of this study was to explore the hypothesis of potential links between microbial translocation and thymic function in HIV-1 patients living in Belgium. The extent of microbial translocation was assessed through the measurement of soluble CD14 (sCD14). T-cell receptor excision circles (sjTRECs and dβTRECs) were used as a measure of thymic function. Data were collected from 75 HIV-infected patients. Simple and complex linear regressions were done to analyze the link between these two processes. We found a statistically relevant negative correlation between thymopoiesis (sjTREC) and sCD14 level (p = 0.004). These results suggest a link between thymic function failure, microbial translocation and innate immune activation.

Idiopathic cluster of differentiation 4⁺ (CD4⁺) T-cell lymphocytopenia is a rare heterogeneous clinical syndrome characterized by low absolute CD4 counts on two different occasions without any evidence of other known cause of immunodeficiency including human immunodeficiency virus (HIV), infections or drugs associated with fall in CD4⁺ count. Also referred to as severe unexplained HIV seronegative immune suppression by the World Health Organization, it was first described by Centers for Disease Control in 1992 in patients with opportunistic infections who were negative for HIV but had low CD4 counts. Patients typically present with opportunistic infections, malignancies, or autoimmune disorders. There have been case reports on opportunistic infections such as cryptococcal meningitis or non-Mycobacterium tuberculosis infections in these patients. However, no case of disseminated M. tuberculosis has been reported as such in Indian literature. We present a case of disseminated tuberculosis with low CD4 counts without any evidence of HIV infection.

• Cryptococcal meningitis
• disseminated tuberculosis
• idiopathic cluster of differentiation 4+ T-cell lymphocytopenia
• immunodeficiency
• opportunistic infections

• HIV/AIDS
• biomarkers
• idiopathic CD4+ lymphopenia
• inflammation
• mucosal immunity

• Adult
• Biopsy
• CD4-Positive T-Lymphocytes/immunology
• Colon/pathology
• Female
• Flow Cytometry
• Humans
• Immune Tolerance
• Immunohistochemistry
• Inflammation
• Intestinal Mucosa/pathology
• Lymphopenia/pathology
• Male
• Middle Aged

• HHSN261200800001C NCI NIH HHS
• HHSN261200800001E NCI NIH HHS
• HHSN261200800001E NCI NIH HHS

The IgG4-related disease is a fibroinflammatory disease characterized by tumefactive lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and, often but not always, elevated serum levels of IgG4. Idiopathic CD4 lymphocytopenia is a heterogenic and rare syndrome characterized by the detection of a persistent absolute CD4 T cells count <300 cells/mm³ (or <20% of total T cells) in more than one occasion and no evidence of HIV infection in absence of immunodeficiency or therapy associated with depressed levels of CD4 T cells. We report the case of a 50-year-old man with a multiorgan IgG4-related disease presenting in a temporal association with a profound and symptomatic idiopathic CD4 lymphocytopenia. Both clinical pictures improved after steroid treatment. Idiopathic CD4 lymphocytopenia has been associated with a number of autoimmune conditions but, to the best of our knowledge, this is the first case in which an association with the IgG4-related disease is reported.

(1→3)-Beta-D-glucan was detected in high levels in cerebrospinal fluid, and to lesser extent in serum, among HIV-infected persons with cryptococcal meningitis.

 (1→3)-β-d-Glucan (BDG) is a helpful diagnostic marker for many invasive fungal infections. However, BDG is not thought to be useful in diagnosing cryptococcosis. We evaluated the utility of BDG as an adjunct diagnostic tool for patients infected with human immunodeficiency virus (HIV) and presenting with suspected cryptococcal meningitis.

 The Fungitell assay was used to measure BDG concentrations in cerebrospinal fluid (CSF) (n = 177) and serum (n = 109) of HIV-infected Ugandans and South Africans with suspected meningitis. Correlations between BDG concentrations and quantitative CSF cryptococcal cultures, CSF cryptococcal antigen (CRAG) titers, and 18 different CSF cytokine concentrations were assessed using non-parametric tests. Mixed models evaluated longitudinal changes in CSF BDG concentrations. Survival analyses were used to evaluate BDG's relationship with mortality.

 The Fungitell BDG assay provided 89% sensitivity and 85% specificity in CSF for cryptococcal meningitis. Serum sensitivity was suboptimal (79%). Cerebrospinal fluid BDG concentrations at diagnosis were median (interquartile range) 343 (200–597) pg/mL in cryptococcal patients and 37 (23–46) pg/mL in patients without cryptococcosis. Sensitivity in CSF improved to 98% (53 of 54) when initial fungal burdens were ≥10 000 colony-forming units/mL. (1→3)-β-d-Glucan normalized rapidly after initiating antifungal therapy. Baseline BDG concentrations correlated with CSF fungal burden (rho = 0.820; P < .001), CSF CRAG lateral flow assay titers (rho = 0.780, P < .001), and monocyte chemotactic protein-1 levels in CSF (P = .047). In patients with cryptococcal meningitis, BDG ≥500 pg/mL at diagnosis was associated with increased 10-week mortality.

 (1→3)-β-d-Glucan is detectable in the CSF of HIV-infected patients with Cryptococcus, and it may provide useful prognostic information. Sensitivity is less than CRAG; however, BDG normalizes rapidly, unlike CRAG, making BDG potentially useful in diagnosing recurrent episodes.

• AIDS
• HIV
• cryptococcal meningitis
• predictive value of tests
• β-glucan

• Giant cell arteritis
• Idiopathic CD4 lymphocytopenia
• Mucormycosis

• T32 CA009677 NCI NIH HHS

• biomarkers
• t cell activation
• monocyte activation
• inflammation
• morbidity
• hiv

• Anti-HIV Agents/therapeutic use
• Biomarkers
• HIV Infections/drug therapy
• HIV Infections/immunology
• HIV Infections/physiopathology
• Humans
• Inflammation
• Lymphocyte Activation
• Monocytes
• T-Lymphocytes

• Z99 AI999999 Intramural NIH HHS

The pathophysiological mechanisms that underlie the progression of human immunodeficiency virus-1 (HIV-1) disease to full-blown AIDS are not well understood. Findings suggest that, during HIV-1 infection, plasma lipopolysaccharide (LPS) levels, which are used as an indicator of microbial translocation (MT), are elevated throughout the acute and chronic phases of HIV-1 disease. The translocation of bacterial products through the damaged gastrointestinal barrier into the systemic circulation has been described as a driver of immune activation. In contrast, comorbidities that are associated with HIV-1 infection have been attributed to chronic inflammation and immune system dysfunction secondary to MT or low-level HIV-1 replication in plasma and cell reservoirs. Moreover, accelerated aging is significantly associated with chronic inflammation, immune activation, and immune senescence. In this review, we aimed to investigate the role of inflammation as a pivotal marker in the pathogenesis of HIV-1 disease. We will discuss the key features of chronic inflammation and immune activation that are observed during the natural course of the disease and those features that are detected in cART-modified infection. The review will focus on the following aspects of HIV-1 infection: (1) MT; (2) the role of residual viremia; and (3) “immune senescence” or “inflammaging.” Many questions remain unanswered about the potential mechanisms that are involved in HIV-1 pathogenesis. Further studies are needed to better investigate the mechanisms that underlie immune activation and their correlation with HIV-1 disease progression.

• Human immunodeficiency virus-1
• Combined antiretroviral therapy
• Immune activation
• Microbial translocation
• Residual viremia
• Immune senescence

Idiopathic CD4 lymphocytopenia (ICL) was first defined in 1992 by the US Centers for Disease Control and Prevention (CDC) as the repeated presence of a CD4+ T lymphocyte count of fewer than 300 cells per cubic millimeter or of less than 20% of total T cells with no evidence of human immunodeficiency virus (HIV) infection and no condition that might cause depressed CD4 counts. Most of our knowledge about ICL comes from scattered case reports. The aim of this study was to collect comprehensive data from the previously published cases to understand the characteristics of this rare condition. We searched the PubMed database and Science Direct for case reports since 1989 for Idiopathic CD4 lymphocytopenia cases. We found 258 cases diagnosed with ICL in 143 published papers. We collected data about age, sex, pathogens, site of infections, CD4 count, CD8 count, CD4:CD8 ratio, presence of HIV risk factors, malignancies, autoimmune diseases and whether the patients survived or died. The mean age at diagnosis of first opportunistic infection (or ICL if no opportunistic infection reported) was 40.7 ± 19.2 years (standard deviation), with a range of 1 to 85. One-sixty (62%) patients were males, 91 (35.2%) were females, and 7 (2.7%) patients were not identified whether males or females. Risk factors for HIV were documented in 36 (13.9%) patients. The mean initial CD4 count was 142.6 ± 103.9/mm³ (standard deviation). The mean initial CD8 count was 295 ± 273.6/mm³ (standard deviation). The mean initial CD4:CD8 ratio was 0.6 ± 0.7 (standard deviation). The mean lowest CD4 count was 115.4 ± 87.1/mm³ (standard deviation). The majority of patients 226 (87.6%) had at least one infection. Cryptococcal infections were the most prevalent infections in ICL patients (26.6%), followed by mycobacterial infections (17%), candidal infections (16.2%), and VZV infections (13.1%). Malignancies were reported in 47 (18.1%) patients. Autoimmune diseases were reported in 37 (14.2%) patients.

• Autoimmune diseases
• idiopathic CD4 lymphocytopenia
• lymphopenia
• opportunistic infections

• inflammatory cytokines
• microbial translocation
• visceral leishmaniasis-HIV/AIDS coinfection

• myalgic encephalomyelitis
• me
• human endogenous retrovirus
• herv
• plasmacytoid dendritic cell
• pdc

• Antibodies, Viral/blood
• Antibodies, Viral/immunology
• Dendritic Cells/immunology
• Dendritic Cells/pathology
• Duodenum/immunology
• Duodenum/pathology
• Fatigue Syndrome, Chronic/immunology
• Fatigue Syndrome, Chronic/pathology
• Fluorescent Antibody Technique, Indirect
• Humans
• Plasma Cells/immunology
• Plasma Cells/pathology
• Retroviridae Proteins/immunology

• R01 AI078234 NIAID NIH HHS
• AI078234 NIAID NIH HHS

• Adolescent
• Adult
• Aged
• CD4 Lymphocyte Count
• CD4-Positive T-Lymphocytes/immunology
• CD4-Positive T-Lymphocytes/metabolism
• Cytokines/immunology
• Cytokines/metabolism
• Cytokines/pharmacology
• Female
• Homeostasis/immunology
• Humans
• Immunophenotyping
• Interleukin-2/immunology
• Interleukin-2/metabolism
• Interleukin-2/pharmacology
• Interleukin-2 Receptor alpha Subunit/metabolism
• Interleukin-7/immunology
• Interleukin-7/metabolism
• Interleukin-7/pharmacology
• Interleukin-7 Receptor alpha Subunit/metabolism
• Lymphocyte Activation
• Lymphopenia/immunology
• Lymphopenia/metabolism
• Male
• Middle Aged
• Phosphorylation/drug effects
• STAT5 Transcription Factor/metabolism
• Young Adult
• Thymic Stromal Lymphopoietin

• hiv
• microbial translocation
• immune activation
• mucosal immunity

• Animals
• Bacterial Physiological Phenomena
• Bacterial Translocation
• Gastrointestinal Tract/immunology
• Gastrointestinal Tract/microbiology
• HIV Infections/complications
• HIV Infections/immunology
• HIV Infections/microbiology
• HIV Infections/pathology
• Humans

• K99 HL108743 NHLBI NIH HHS
• Y99 AI999999 NIAID NIH HHS
• Z99 AI999999 Intramural NIH HHS
• ZIA AI001029-04 Intramural NIH HHS

Microbial translocation (MT) is the process by which microbes or microbial products translocate from the intestine to the systemic circulation. MT is a common cause of systemic immune activation in HIV infection and is associated with reduced frequencies of CD4⁺ T cells; no data exist, however, on the role of MT in intestinal helminth infections.

We measured the plasma levels of MT markers, acute-phase proteins, and pro- and anti - inflammatory cytokines in individuals with or without hookworm infections. We also estimated the absolute counts of CD4⁺ and CD8⁺ T cells as well as the frequencies of memory T cell and dendritic cell subsets. Finally, we also measured the levels of all of these parameters in a subset of individuals following treatment of hookworm infection.

Our data suggest that hookworm infection is characterized by increased levels of markers associated with MT but not acute-phase proteins nor pro-inflammatory cytokines. Hookworm infections were also associated with increased levels of the anti – inflammatory cytokine – IL-10, which was positively correlated with levels of lipopolysaccharide (LPS). In addition, MT was associated with decreased numbers of CD8⁺ T cells and diminished frequencies of particular dendritic cell subsets. Antihelmintic treatment of hookworm infection resulted in reversal of some of the hematologic and microbiologic alterations.

Our data provide compelling evidence for MT in a human intestinal helminth infection and its association with perturbations in the T cell and antigen-presenting cell compartments of the immune system. Our data also reveal that at least one dominant counter-regulatory mechanism i.e. increased IL-10 production might potentially protect against systemic immune activation in hookworm infections.

Hookworm infections affect more than half a billion people worldwide and cause morbidity in the form of intestinal injury and blood loss. Host immunologic factors that influence the pathogenesis of disease in these individuals are not completely understood. Circulating microbial products such as LPS and markers associated with microbial translocation (transfer of microbes or microbial products from the intestine to the circulation) have been shown to play an important role in disease pathogenesis of certain infections like HIV. We have attempted to elucidate the role of the above mentioned factors in disease pathogenesis by comparing the plasma levels of the various markers in a group of hookworm infected and uninfected individuals. We show that circulating levels of microbial translocation markers are elevated in hookworm infected individuals, a potential cause of morbidity in these infections. This is associated with changes in the host immune system, especially in terms of lymphocyte and dendritic cells subsets. However, microbial translocation is not accompanied by increased levels of acute phase proteins or pro-inflammatory cytokines indicating that the parasite has evolved mechanisms to dampen LPS induced inflammation. Thus, our study highlights a novel pathway of pathogenesis in an intestinal helminth infection and improves our understanding of the various factors involved in the complex host-parasite interaction.

• Antigen-Presenting Cells/immunology
• Bacterial Translocation
• Hookworm Infections/complications
• Hookworm Infections/immunology
• Hookworm Infections/pathology
• Humans
• Lymphocyte Count
• Prospective Studies
• T-Lymphocyte Subsets/immunology
• T-Lymphocytes/immunology

• Intramural NIH HHS

The environmental conditions that could lead to an increased risk for the development of an infection during prolonged space flight include: microgravity, stress, radiation, disturbance of circadian rhythms, and altered nutritional intake. A large body of literature exists on the impairment of the immune system by space flight. With the advent of missions outside the Earth's magnetic field, the increased risk of adverse effects due to exposure to radiation from a solar particle event (SPE) needs to be considered. Using models of reduced gravity and SPE radiation, we identify that either 2 Gy of radiation or hindlimb suspension alone leads to activation of the innate immune system and the two together are synergistic. The mechanism for the transient systemic immune activation is a reduced ability of the GI tract to contain bacterial products. The identification of mechanisms responsible for immune dysfunction during extended space missions will allow the development of specific countermeasures.

• Animals
• Bacterial Translocation/physiology
• Female
• Gastrointestinal Tract/immunology
• Gastrointestinal Tract/microbiology
• Hindlimb Suspension
• Mice
• Mice, Inbred ICR
• Solar Activity

Idiopathic CD4 lymphocytopenia (ICL) is a presumed heterogenous syndrome with key element low CD4 T-cell counts (below 300/mm³) without evidence of HIV infection or other known immunodeficiency. The etiology, pathogenesis, and management of ICL remain poorly understood and inadequately defined. The clinical presentation can range from serious opportunistic infections to incidentally diagnosed asymptomatic individuals. Cryptococcal and non-tuberculous mycobacterial infections and progressive multifocal leukoencephalopathy are the most significant presenting infections, although the spectrum of opportunistic diseases can be similar to that in patients with lymphopenia and HIV infection. Malignancy is common and related to opportunistic pathogens with an oncogenic potential. Autoimmune diseases are also seen in ICL with an increased incidence. The etiology of ICL is unknown. Mechanisms implicated in CD4 reduction may include decreased production, increased destruction, and tissue sequestration. New distinct genetic defects have been identified in certain patients with ICL, supporting the hypothesis of the lack of a common etiology in this syndrome. The management of ICL is focused on the treatment of opportunistic infections, appropriate prophylactic antibiotics, and close monitoring. In selected patients with life-threatening infections or profound immunodeficiency, strategies to increase T-cell counts or enhance immune function could be considered and have included interleukin-2, interferon-gamma, interleukin-7, and hematopoietic stem cell transplantation. The prognosis is influenced by the accompanying opportunistic infections and may be affected by publication bias of severe cases with unfavorable outcomes. As newer laboratory investigation techniques are being developed and targeted experimental treatments become available, our comprehension and prognosis of this rare syndrome could be significantly improved.

• Adult
• Female
• Humans
• Interleukin-7/blood
• Interleukin-7/genetics
• Interleukin-7/immunology
• Leukocytes, Mononuclear/metabolism
• Lymphocyte Count
• Male
• Middle Aged
• Phosphorylation
• Real-Time Polymerase Chain Reaction
• Receptors, Interleukin-7/blood
• Receptors, Interleukin-7/genetics
• Receptors, Interleukin-7/immunology
• STAT5 Transcription Factor/genetics
• STAT5 Transcription Factor/metabolism
• T-Lymphocytes/immunology
• T-Lymphocytopenia, Idiopathic CD4-Positive/immunology
• T-Lymphocytopenia, Idiopathic CD4-Positive/metabolism
• Up-Regulation
• bcl-2-Associated X Protein/genetics
• bcl-2-Associated X Protein/metabolism

• HHSN261200800001C NCI NIH HHS
• HHSN261200800001E NCI NIH HHS

• Adult
• Antiretroviral Therapy, Highly Active
• Antiviral Agents/administration & dosage
• Antiviral Agents/pharmacology
• Bromodeoxyuridine/administration & dosage
• Bromodeoxyuridine/pharmacology
• CD4-Positive T-Lymphocytes/drug effects
• CD4-Positive T-Lymphocytes/pathology
• CD4-Positive T-Lymphocytes/physiology
• CD8-Positive T-Lymphocytes/pathology
• CD8-Positive T-Lymphocytes/physiology
• Cell Proliferation/drug effects
• Female
• HIV Infections/drug therapy
• HIV Infections/immunology
• HIV Infections/virology
• HIV-1/drug effects
• HIV-1/growth & development
• HIV-1/immunology
• HIV-1/physiology
• Humans
• Immunologic Memory/drug effects
• Immunologic Memory/physiology
• Lymphocyte Count
• Male
• Middle Aged
• Viral Load/drug effects
• Viral Load/physiology
• Young Adult

• HHSN261200800001C CCR NIH HHS
• HHSN261200800001E NCI NIH HHS
• Intramural NIH HHS

Visceral leishmaniasis (VL) is characterized by parasite-specific immunosuppression besides an intense pro-inflammatory response. Lipopolisaccharide (LPS) has been implicated in the immune activation of T-cell deficient diseases such as HIV/AIDS and idiopathic lymphocytopenia. The source of LPS is gram-negative bacteria that enter the circulation because of immunological mucosal barrier breakdown. As gut parasitization also occurs in VL, it was hypothesized that LPS may be elevated in leishmaniasis, contributing to cell activation.

Flow cytometry analysis and immunoassays (ELISA and luminex micro-beads system) were used to quantify T-cells and soluble factors. Higher LPS and soluble CD14 levels were observed in active VL in comparison to healthy subjects, indicating that LPS was bioactive; there was a positive correlation between these molecules (r = 0.61;p<0.05). Interestingly, LPS was negatively correlated with CD4⁺ (r = −0.71;p<0.01) and CD8⁺ T-cells (r = −0.65;p<0.05). Moreover, higher levels of activation-associated molecules (HLA-DR, CD38, CD25) were seen on T lymphocytes, which were positively associated with LPS levels. Pro-inflammatory cytokines and macrophage migration inhibitory factor (MIF) were also augmented in VL patients. Consistent with the higher immune activation status, LPS levels were positively correlated with the inflammatory cytokines IL-6 (r = 0.63;p<0.05), IL-8 (r = 0.89;p<0.05), and MIF (r = 0.64;p<0.05). Also, higher plasma intestinal fatty acid binding protein (IFABP) levels were observed in VL patients, which correlated with LPS levels (r = 0.57;p<0.05).

Elevated levels of LPS in VL, in correlation with T-cell activation and elevated pro-inflammatory cytokines and MIF indicate that this bacterial product may contribute to the impairment in immune effector function. The cytokine storm and chronic immune hyperactivation status may contribute to the observed T-cell depletion. LPS probably originates from microbial translocation as suggested by IFABP levels and, along with Leishmania antigen-mediated immune suppression, may play a role in the immunopathogenesis of VL. These findings point to possible benefits of antimicrobial prophylaxis in conjunction with anti-Leishmania therapy.

Visceral leishmaniasis (VL) affects organs rich in lymphocytes, being characterized by intense Leishmania-induced T-cell depletion and reduction in other hematopoietic cells. In other infectious and non-infectious diseases in which the immune system is affected, such as HIV-AIDS and inflammatory bowel disease, damage to gut-associated lymphocyte tissues occurs, enabling luminal bacteria to enter into the circulation. Lipopolisaccharide (LPS) is a bacterial product that stimulates macrophages, leading to the production of pro-inflammatory cytokines and other soluble factors such as MIF, which in turn activate lymphocytes. Continuous and exaggerated stimulation causes exhaustion of the T-cell compartment, contributing to immunosuppression.

Herein, we show that an increment in LPS plasma levels also occurs in VL; the higher the LPS levels, the lower the TCD4⁺ and TCD8⁺ cell count in the blood. This T-cell depletion may affect the mucosal immune system, which, along with intestinal parasitization by amastigotes, may contribute to gut barrier damage and consequent microbial translocation. LPS levels were correlated with T-cell activation, pro-inflammatory cytokine plasma levels, MIF, and IFABP, showing that a bacterial molecule, probably from luminal origin, not associated with Leishmania infection can negatively affect the immune system. These findings points to possible benefits of antimicrobial prophylaxis in conjunction with anti-Leishmania therapy.

• Adolescent
• Adult
• Bacteria/immunology
• Bacterial Translocation/immunology
• Cytokines/blood
• Female
• Flow Cytometry
• Humans
• Immunoassay
• Intramolecular Oxidoreductases/blood
• Leishmania/pathogenicity
• Leishmaniasis, Visceral/immunology
• Lipopolysaccharides/immunology
• Lymphocyte Activation
• Lymphocyte Count
• Macrophage Migration-Inhibitory Factors/blood
• Male
• Middle Aged
• Young Adult

Microbial translocation may contribute to the immunopathogenesis in HIV infection. We investigated if microbial translocation and inflammation were associated with innate and adaptive immune responses in adults with HIV.

This was an observational cohort study. Sera from HIV-infected and HIV-uninfected individuals were analyzed for microbial translocation (soluble CD14, lipopolysaccharides [LPS], endotoxin core antibody, and anti-α-galactosyl antibodies) and inflammatory markers (high sensitivity C-reactive protein, IL-6, IL-1 receptor antagonist, soluble tumor necrosis factor receptor II, and IL-10) with enzyme-linked immunosorbent assays. Peripheral blood mononuclear cells (PBMC) from HIV-infected persons and healthy controls (primed with single-stranded HIV-1-derived RNA) were stimulated with LPS, and cytokine production was measured. Finally, HIV-infected patients were immunized with Prevnar 7vPnC±CpG 7909 followed by Pneumo Novum PPV-23. Effects of microbial translocation and inflammation on immunization were analyzed in a predictive regression model. We included 96 HIV-infected individuals, 76 on highly active antiretroviral therapy (HAART), 20 HAART-naive, and 50 healthy controls. Microbial translocation and inflammatory markers were higher among HIV-infected persons than controls. Cytokine levels following LPS stimulation were increased in PBMCs from HAART-naive compared to HAART-treated HIV-infected persons. Further, RNA-priming of PBMCs from controls acted synergistically with LPS to augment cytokine responses. Finally, high serum LPS levels predicted poor vaccine responses among HAART-naive, but not among HAART-treated HIV-infected individuals.

LPS acts synergistically with HIV RNA to stimulate innate immune responses in vitro and increasing serum LPS levels seem to predict poor antibody responses after vaccination among HAART-naive HIV-infected persons. Thus, our results suggest that microbial translocation may be associated with innate and adaptive immune dysfunction in untreated HIV infection.

• hiv-1
• toll-like receptors
• monocytes
• lps
• microbial translocation

• Cell Line
• Cells, Cultured
• Disease Progression
• Female
• Flow Cytometry
• HIV Infections/immunology
• HIV Infections/metabolism
• HIV Infections/virology
• HIV-1/physiology
• Humans
• Ligands
• Lymphocyte Activation/immunology
• Male
• Monocytes
• RNA, Viral
• Toll-Like Receptor 8/physiology
• Tumor Necrosis Factor-alpha/immunology
• Tumor Necrosis Factor-alpha/metabolism
• Viral Load

• P01 AI074415 NIAID NIH HHS
• R21 AI071806 NIAID NIH HHS
• Howard Hughes Medical Institute
• HHSN266200400088C PHS HHS

• hiv-1
• microbial translocation
• monocyte/macrophage
• systemic immune activation
• children and adolescents
• lipopolysaccharide
• inflammation

• Adolescent
• Antiretroviral Therapy, Highly Active
• Bacterial Translocation
• CD4 Lymphocyte Count
• Child
• Child, Preschool
• Cross-Sectional Studies
• Female
• HIV Infections/blood
• HIV Infections/drug therapy
• HIV Infections/immunology
• HIV-1/immunology
• HIV-1/physiology
• Humans
• Infant
• Lipopolysaccharide Receptors/blood
• Macrophage Activation/immunology
• Male
• Tumor Necrosis Factor Receptor Superfamily, Member 7/blood
• Tumor Necrosis Factor-alpha/blood
• Viral Load
• Virus Replication/immunology

• R01 AI065265 NIAID NIH HHS
• T32 AR007603 NIAMS NIH HHS
• R01 HD032259 NICHD NIH HHS
• R01 AI047723 NIAID NIH HHS
• AI065265 NIAID NIH HHS
• AI047723 NIAID NIH HHS
• HD032259 NICHD NIH HHS

• immune activation
• th17
• type i interferons
• homeostasis
• t cells

• Animals
• HIV Infections/immunology
• HIV Infections/pathology
• Host-Pathogen Interactions
• Humans
• Interferon Type I/immunology
• Simian Acquired Immunodeficiency Syndrome/immunology
• Simian Acquired Immunodeficiency Syndrome/pathology
• T-Lymphocyte Subsets/immunology

• Z01 AI000585 Intramural NIH HHS
• Z99 AI999999 Intramural NIH HHS