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Kabakibo TS, Arnold E, Padhan K, Lemieux A, Ortega-Delgado GG, Routy JP, Shoukry N, Dubé M, Kaufmann DE. Artificial antigen-presenting cell system reveals CD28's role in modulating T cell functions during human immunodeficiency virus infection. iScience 2024; 27:110947. [PMID: 39381752 PMCID: PMC11460474 DOI: 10.1016/j.isci.2024.110947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 02/16/2024] [Accepted: 09/10/2024] [Indexed: 10/10/2024] Open
Abstract
T cell immune dysfunction is a prominent feature of chronic HIV infection. To evaluate non-specific dysfunction, a method involving both generic activation and T cell receptor (TCR) stimulation is necessary. We created a tunable artificial antigen-presenting cell (aAPC) system. This system consists of lipid bilayers on cytometry-compatible silica microbeads (5 μm). When only anti-CD3 is incorporated, T cell activation is limited. Introducing anti-CD28 agonists significantly elevates the cytokine expression and upregulation of activation-induced markers. CD28 co-stimulation modulates the response profile, preferentially promoting IL-2 expression relative to other cytokines. aAPCs-stimulated CD4+ and CD8+ T cells from untreated HIV-infected individuals exhibit altered effector functions and diminished CD28 dependence. These functions are skewed toward TNFα, IFNγ and CD107a, with reduced IL-2. Antiretroviral therapy partially normalizes this distorted profile in CD4+ T cells, but not in CD8+ T cells. Our findings show T cell intrinsic biases that may contribute to persistent systemic T cell dysfunction associated with HIV pathogenesis.
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Affiliation(s)
- Tayma Shaaban Kabakibo
- Research Centre of the Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Université de Montréal, Montréal, QC, Canada
- Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC H2X 0A9, Canada
| | - Edwige Arnold
- Research Centre of the Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Université de Montréal, Montréal, QC, Canada
| | - Kartika Padhan
- Research Centre of the Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Audrée Lemieux
- Research Centre of the Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Université de Montréal, Montréal, QC, Canada
- Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC H2X 0A9, Canada
| | | | - Jean-Pierre Routy
- Chronic Viral Illnesses Service and Division of Hematology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montreal, QC, Canada
| | - Naglaa Shoukry
- Research Centre of the Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Université de Montréal, Montréal, QC, Canada
- Département de Médecine, Université de Montréal, Montréal, QC H2X 0A9, Canada
| | - Mathieu Dubé
- Research Centre of the Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Daniel E. Kaufmann
- Research Centre of the Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Université de Montréal, Montréal, QC, Canada
- Département de Médecine, Université de Montréal, Montréal, QC H2X 0A9, Canada
- Division of Infectious Diseases, Department of Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
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Le Hingrat Q, Sereti I, Landay AL, Pandrea I, Apetrei C. The Hitchhiker Guide to CD4 + T-Cell Depletion in Lentiviral Infection. A Critical Review of the Dynamics of the CD4 + T Cells in SIV and HIV Infection. Front Immunol 2021; 12:695674. [PMID: 34367156 PMCID: PMC8336601 DOI: 10.3389/fimmu.2021.695674] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 06/09/2021] [Indexed: 01/02/2023] Open
Abstract
CD4+ T-cell depletion is pathognomonic for AIDS in both HIV and simian immunodeficiency virus (SIV) infections. It occurs early, is massive at mucosal sites, and is not entirely reverted by antiretroviral therapy (ART), particularly if initiated when T-cell functions are compromised. HIV/SIV infect and kill activated CCR5-expressing memory and effector CD4+ T-cells from the intestinal lamina propria. Acute CD4+ T-cell depletion is substantial in progressive, nonprogressive and controlled infections. Clinical outcome is predicted by the mucosal CD4+ T-cell recovery during chronic infection, with no recovery occurring in rapid progressors, and partial, transient recovery, the degree of which depends on the virus control, in normal and long-term progressors. The nonprogressive infection of African nonhuman primate SIV hosts is characterized by partial mucosal CD4+ T-cell restoration, despite high viral replication. Complete, albeit very slow, recovery of mucosal CD4+ T-cells occurs in controllers. Early ART does not prevent acute mucosal CD4+ T-cell depletion, yet it greatly improves their restoration, sometimes to preinfection levels. Comparative studies of the different models of SIV infection support a critical role of immune activation/inflammation (IA/INFL), in addition to viral replication, in CD4+ T-cell depletion, with immune restoration occurring only when these parameters are kept at bay. CD4+ T-cell depletion is persistent, and the recovery is very slow, even when both the virus and IA/INFL are completely controlled. Nevertheless, partial mucosal CD4+ T-cell recovery is sufficient for a healthy life in natural hosts. Cell death and loss of CD4+ T-cell subsets critical for gut health contribute to mucosal inflammation and enteropathy, which weaken the mucosal barrier, leading to microbial translocation, a major driver of IA/INFL. In turn, IA/INFL trigger CD4+ T-cells to become either viral targets or apoptotic, fueling their loss. CD4+ T-cell depletion also drives opportunistic infections, cancers, and comorbidities. It is thus critical to preserve CD4+ T cells (through early ART) during HIV/SIV infection. Even in early-treated subjects, residual IA/INFL can persist, preventing/delaying CD4+ T-cell restoration. New therapeutic strategies limiting mucosal pathology, microbial translocation and IA/INFL, to improve CD4+ T-cell recovery and the overall HIV prognosis are needed, and SIV models are extensively used to this goal.
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Affiliation(s)
- Quentin Le Hingrat
- Division of Infectious Diseases, DOM, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Irini Sereti
- HIV Pathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Alan L Landay
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL, United States
| | - Ivona Pandrea
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Infectious Diseases and Immunology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
| | - Cristian Apetrei
- Division of Infectious Diseases, DOM, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Infectious Diseases and Immunology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
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Wong K, Nguyen J, Blair L, Banjanin M, Grewal B, Bowman S, Boyd H, Gerstner G, Cho HJ, Panfilov D, Tam CK, Aguilar D, Venketaraman V. Pathogenesis of Human Immunodeficiency Virus- Mycobacterium tuberculosis Co-Infection. J Clin Med 2020; 9:E3575. [PMID: 33172001 PMCID: PMC7694603 DOI: 10.3390/jcm9113575] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 11/02/2020] [Accepted: 11/04/2020] [Indexed: 02/07/2023] Open
Abstract
Given that infection with Mycobacterium tuberculosis (Mtb) is the leading cause of death amongst individuals living with HIV, understanding the complex mechanisms by which Mtb exacerbates HIV infection may lead to improved treatment options or adjuvant therapies. While it is well-understood how HIV compromises the immune system and leaves the host vulnerable to opportunistic infections such as Mtb, less is known about the interplay of disease once active Mtb is established. This review explores how glutathione (GSH) depletion, T cell exhaustion, granuloma formation, and TNF-α upregulation, as a result of Mtb infection, leads to an increase in HIV disease severity. This review also examines the difficulties of treating coinfected patients and suggests further research on the clinical use of GSH supplementation.
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Affiliation(s)
- Kevin Wong
- College of Osteopathic Medicine of the Pacific-NorthWest, Western University of Health Sciences, Lebanon, OR 97355, USA; (K.W.); (J.N.); (L.B.); (M.B.); (B.G.); (S.B.); (H.B.); (G.G.); (H.J.C.); (D.P.); (C.K.T.); (D.A.)
| | - James Nguyen
- College of Osteopathic Medicine of the Pacific-NorthWest, Western University of Health Sciences, Lebanon, OR 97355, USA; (K.W.); (J.N.); (L.B.); (M.B.); (B.G.); (S.B.); (H.B.); (G.G.); (H.J.C.); (D.P.); (C.K.T.); (D.A.)
| | - Lillie Blair
- College of Osteopathic Medicine of the Pacific-NorthWest, Western University of Health Sciences, Lebanon, OR 97355, USA; (K.W.); (J.N.); (L.B.); (M.B.); (B.G.); (S.B.); (H.B.); (G.G.); (H.J.C.); (D.P.); (C.K.T.); (D.A.)
| | - Marina Banjanin
- College of Osteopathic Medicine of the Pacific-NorthWest, Western University of Health Sciences, Lebanon, OR 97355, USA; (K.W.); (J.N.); (L.B.); (M.B.); (B.G.); (S.B.); (H.B.); (G.G.); (H.J.C.); (D.P.); (C.K.T.); (D.A.)
| | - Bunraj Grewal
- College of Osteopathic Medicine of the Pacific-NorthWest, Western University of Health Sciences, Lebanon, OR 97355, USA; (K.W.); (J.N.); (L.B.); (M.B.); (B.G.); (S.B.); (H.B.); (G.G.); (H.J.C.); (D.P.); (C.K.T.); (D.A.)
| | - Shane Bowman
- College of Osteopathic Medicine of the Pacific-NorthWest, Western University of Health Sciences, Lebanon, OR 97355, USA; (K.W.); (J.N.); (L.B.); (M.B.); (B.G.); (S.B.); (H.B.); (G.G.); (H.J.C.); (D.P.); (C.K.T.); (D.A.)
| | - Hailey Boyd
- College of Osteopathic Medicine of the Pacific-NorthWest, Western University of Health Sciences, Lebanon, OR 97355, USA; (K.W.); (J.N.); (L.B.); (M.B.); (B.G.); (S.B.); (H.B.); (G.G.); (H.J.C.); (D.P.); (C.K.T.); (D.A.)
| | - Grant Gerstner
- College of Osteopathic Medicine of the Pacific-NorthWest, Western University of Health Sciences, Lebanon, OR 97355, USA; (K.W.); (J.N.); (L.B.); (M.B.); (B.G.); (S.B.); (H.B.); (G.G.); (H.J.C.); (D.P.); (C.K.T.); (D.A.)
| | - Hyun Jun Cho
- College of Osteopathic Medicine of the Pacific-NorthWest, Western University of Health Sciences, Lebanon, OR 97355, USA; (K.W.); (J.N.); (L.B.); (M.B.); (B.G.); (S.B.); (H.B.); (G.G.); (H.J.C.); (D.P.); (C.K.T.); (D.A.)
| | - David Panfilov
- College of Osteopathic Medicine of the Pacific-NorthWest, Western University of Health Sciences, Lebanon, OR 97355, USA; (K.W.); (J.N.); (L.B.); (M.B.); (B.G.); (S.B.); (H.B.); (G.G.); (H.J.C.); (D.P.); (C.K.T.); (D.A.)
| | - Cho Ki Tam
- College of Osteopathic Medicine of the Pacific-NorthWest, Western University of Health Sciences, Lebanon, OR 97355, USA; (K.W.); (J.N.); (L.B.); (M.B.); (B.G.); (S.B.); (H.B.); (G.G.); (H.J.C.); (D.P.); (C.K.T.); (D.A.)
| | - Delaney Aguilar
- College of Osteopathic Medicine of the Pacific-NorthWest, Western University of Health Sciences, Lebanon, OR 97355, USA; (K.W.); (J.N.); (L.B.); (M.B.); (B.G.); (S.B.); (H.B.); (G.G.); (H.J.C.); (D.P.); (C.K.T.); (D.A.)
| | - Vishwanath Venketaraman
- College of Osteopathic Medicine of the Pacific-NorthWest, Western University of Health Sciences, Lebanon, OR 97355, USA; (K.W.); (J.N.); (L.B.); (M.B.); (B.G.); (S.B.); (H.B.); (G.G.); (H.J.C.); (D.P.); (C.K.T.); (D.A.)
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
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Nazifi N, Tahmoorespur M, Sekhavati MH, Haghparast A, Behroozikhah MA. Assessment of Signal Peptides to Optimize Interleukin 2 (IL-2) Folding and Expression. CURR PROTEOMICS 2019. [DOI: 10.2174/1570164615666181024113612] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:Using a bacterial expression system such as Escherichia coli (E. coli) is very common for protein expression because of its simplicity, low cost and high efficiency.Objective:In order to express proteins that contain di-sulfide bands, an oxidative space such as the periplasmic environment of the bacteria is required. Therefore, a leader sequence which named Signal Peptide (SP) is needed to direct recombinant protein to fold in periplasmic space. Interleukin-2 (IL-2) is a prominent cytokine which known as growth factor for T-cells and typically produced by a variety of immune cells that stimulate and regulate inflammatory and immune responses.Methods:This study was designed to predict the best signal peptides to express IL-2 in E. coli. To predict the best signal peptides for the expression of IL-2 in Gram-negative bacteria (E. coli), forty-five sequences of SPs were extracted from data base. Some most important details such as n, h and c regions of signal peptides and their probability were studied through the signalP software. </P><P> Afterwards, physico–chemical features of SPs were analyzed by Portparam and Solpro tools. Finally, secretion-pathway and sub-cellular localization sites were evaluated by PRED-TAT and ProtcompB softwares.Results:At the end of the in-silico analyzes, it was determined that ccmH, PelB, traU, yohN, lolA, yhcN are the most reliable SPs, respectively, with highest score and best performing to express the IL-2 protein in E. coli.
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Affiliation(s)
- Narges Nazifi
- Department of Animal Science, Faculty of Agriculture, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Mojtaba Tahmoorespur
- Department of Animal Science, Faculty of Agriculture, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Mohammad Hadi Sekhavati
- Department of Animal Science, Faculty of Agriculture, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Alireza Haghparast
- Pathobiology Department, School of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Mohammad Ali Behroozikhah
- Department of Brucellosis, Razi Vaccine and Serum Research Institute, Agricultural Research Education and Extension Organization (AREEO), Karaj, Iran
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5
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Pawlak EN, Dirk BS, Jacob RA, Johnson AL, Dikeakos JD. The HIV-1 accessory proteins Nef and Vpu downregulate total and cell surface CD28 in CD4 + T cells. Retrovirology 2018; 15:6. [PMID: 29329537 PMCID: PMC5767034 DOI: 10.1186/s12977-018-0388-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 12/20/2017] [Indexed: 12/20/2022] Open
Abstract
Background The HIV-1 accessory proteins Nef and Vpu alter cell surface levels of multiple host proteins to modify the immune response and increase viral persistence. Nef and Vpu can downregulate cell surface levels of the co-stimulatory molecule CD28, however the mechanism of this function has not been completely elucidated. Results Here, we provide evidence that Nef and Vpu decrease cell surface and total cellular levels of CD28. Moreover, using inhibitors we implicate the cellular degradation machinery in the downregulation of CD28. We shed light on the mechanisms of CD28 downregulation by implicating the Nef LL165 and DD175 motifs in decreasing cell surface CD28 and Nef DD175 in decreasing total cellular CD28. Moreover, the Vpu LV64 and S52/56 motifs were required for cell surface CD28 downregulation, while, unlike for CD4 downregulation, Vpu W22 was dispensable. The Vpu S52/56 motif was also critical for Vpu-mediated decreases in total CD28 protein level. Finally, the ability of Vpu to downregulate CD28 is conserved between multiple group M Vpu proteins and infection with viruses encoding or lacking Nef and Vpu have differential effects on activation upon stimulation. Conclusions We report that Nef and Vpu downregulate cell surface and total cellular CD28 levels. We identified inhibitors and mutations within Nef and Vpu that disrupt downregulation, shedding light on the mechanisms utilized to downregulate CD28. The conservation and redundancy between the abilities of two HIV-1 proteins to downregulate CD28 highlight the importance of this function, which may contribute to the development of latently infected cells. Electronic supplementary material The online version of this article (10.1186/s12977-018-0388-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Emily N Pawlak
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Building, Room 3007J, London, ON, N6A 5C1, Canada
| | - Brennan S Dirk
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Building, Room 3007J, London, ON, N6A 5C1, Canada
| | - Rajesh Abraham Jacob
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Building, Room 3007J, London, ON, N6A 5C1, Canada
| | - Aaron L Johnson
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Building, Room 3007J, London, ON, N6A 5C1, Canada
| | - Jimmy D Dikeakos
- Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, University of Western Ontario, Dental Sciences Building, Room 3007J, London, ON, N6A 5C1, Canada.
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6
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Marone G, Varricchi G, Loffredo S, Galdiero MR, Rivellese F, de Paulis A. Are Basophils and Mast Cells Masters in HIV Infection? Int Arch Allergy Immunol 2016; 171:158-165. [PMID: 27960171 DOI: 10.1159/000452889] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
The World Health Organization AIDS epidemic update estimates that more than 37 million people are living with HIV infection. Despite the unprecedented success of antiretroviral treatments, significant challenges remain in the fight against HIV. In particular, how uninfected cells capture HIV and transmit virions to target cells remains an unanswered question. Tissue mast cells and peripheral blood basophils can be exposed to virions or HIV products during infection. Several HIV proteins (i.e., envelope glycoproteins gp120 and gp41, Tat, and Nef) can interact with distinct surface receptors expressed by human basophils and mast cells and modulate their functional responses at different levels. Additionally, several groups have provided evidence that human mast cells can be infected in vitro, as well as in vivo, by certain strains of HIV. Recently, it has been demonstrated that basophils purified from healthy donors and intestinal mast cells can efficiently capture HIV on their cell surface and, cocultured with CD4+ T cells, they can transfer the virus to the cocultured cells leading to infection. Direct contact between human basophils or intestinal mast cells and CD4+ T cells can mediate viral trans-infection of T cells through the formation of viral synapses. Thus, basophils and mast cells can provide a cellular basis for capturing and then spreading viruses throughout the body. Collectively, these findings suggest that human basophils and mast cells play a complex and possibly distinct role in HIV infection, warranting further investigations.
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Affiliation(s)
- Gianni Marone
- Department of Translational Medical Sciences (DiSMeT), University of Naples Federico II, Naples, Italy
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7
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Maternal HIV infection alters the immune balance in the mother and fetus; implications for pregnancy outcome and infant health. Curr Opin HIV AIDS 2016; 11:138-45. [PMID: 26679415 DOI: 10.1097/coh.0000000000000239] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
PURPOSE OF REVIEW With the rapid roll-out of combination antiretroviral therapy to prevent mother-to-child transmission of HIV, there is an annual increase in the number of uninfected infants born to HIV-infected women. Although the introduction of combination antiretroviral therapy has vastly improved pregnancy outcome and the health of infants born to HIV-infected women, concerns remain regarding the impact the maternal HIV infection on the pregnancy outcome and the health of HIV-exposed uninfected infants. RECENT FINDINGS Maternal HIV infection is associated with negative pregnancy outcomes such as low birth weight. In addition, an increased susceptibility to infections is reported in HIV-exposed uninfected infants compared with infants born to uninfected women. Studies have shown that HIV-exposure affects the maternal/fetal unit, with increase of proinflammatory cytokine produced by placental cells, as well as altered infant immune responses. These changes could provide the underlying conditions for negative pregnancy outcomes and facilitate mother-to-child transmission of HIV in the infant. Further studies are required to understand the underlying mechanisms and investigate whether these altered infant immune responses persist and have clinical consequences beyond childhood. SUMMARY HIV infection in pregnant women is associated with altered immune responses in HIV-infected women and their offspring with clinical consequences for pregnancy outcome and the HIV-exposed uninfected infant. Further studies are required to address the origin and long-term consequences of prenatal HIV-exposure and subsequent immune activation for infant health.
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Sachithanandham J, Ramalingam VV, Raja J, Abraham OC, Pulimood SA, Kannangai R. Expression of cytokine-mRNA in peripheral blood mononuclear cell of human immunodeficiency virus-1 subtype C infected individuals with opportunistic viral infections from India (South). Indian J Med Microbiol 2016; 34:76-81. [PMID: 26776123 DOI: 10.4103/0255-0857.174118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Human immunodeficiency virus (HIV) disease progression is associated with a marked change in the level of plasma cytokines. The study reported here investigated the level of mRNA expression of different cytokines: Tumour necrosis factor-alpha (TNF-α), interferon (INF)-gamma, interleukin-10 (IL-10) and IL-21 in the peripheral blood mononuclear cell among the antiretroviral therapy naive subtype C HIV-1 infected individuals and normal healthy controls by real time polymerase chain reaction. The mRNA expressions of all the 4 cytokines in HIV-1 infected individuals were significantly higher compared to healthy controls (P value range 0.0004-0.01). The mean level of IL-10, INF-gamma and TNF-α were higher in HIV infected individuals with low CD4 counts (<300 cells/μl). The IL-10 expression showed a significant negative correlation with CD4 counts (r=-0.25, P=0.04) while IL-21 showed a positive correlation with CD4 counts (r=0.26, P=0.03). There was a significant negative correlation between the cytomegalovirus (CMV) viral load and IL-21 expression. Cytokine levels by mRNA detection avoids the inherent problem of measuring plasma level and this study also provide information on the cytokine levels and CD4+ T cell level among HIV-1 subtype C infected individuals with opportunistic viral infections like CMV.
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Affiliation(s)
| | | | | | | | | | - R Kannangai
- Department of Clinical Virology, Christian Medical College, Vellore, Tamil Nadu, India
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Altfeld M, Bunders MJ. Impact of HIV-1 infection on the feto-maternal crosstalk and consequences for pregnancy outcome and infant health. Semin Immunopathol 2016; 38:727-738. [PMID: 27392971 DOI: 10.1007/s00281-016-0578-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 06/16/2016] [Indexed: 12/21/2022]
Abstract
Adaptation of the maternal immune system to establish maternal/fetal equilibrium is required for a successful pregnancy. Viral infections, including HIV-1 infection, can alter this maternal/fetal equilibrium, with significant consequences for pregnancy outcome, including miscarriages, impaired fetal growth, and premature delivery. Furthermore, maternal HIV-1 infection has been shown to have a long-term impact on the developing fetal immune system also when the infant is not infected with the virus. In this review, we discuss the consequences of maternal HIV-1 infection and antiretroviral therapy on pregnancy outcome and the health of the uninfected HIV-1-exposed infant.
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Affiliation(s)
- Marcus Altfeld
- Department of Virus Immunology, Heinrich-Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Madeleine J Bunders
- Department of Virus Immunology, Heinrich-Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany. .,Department of Experimental Immunology, University of Amsterdam (UvA), Academic Medical Center (AMC), Amsterdam, The Netherlands. .,Emma Childrens Hospital,UvA, AMC, Amsterdam, The Netherlands.
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10
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Iavicoli I, Marinaccio A, Castellino N, Carelli G. Altered Cytokine Production in Mice Exposed to Lead Acetate. Int J Immunopathol Pharmacol 2016; 17:97-102. [PMID: 15345199 DOI: 10.1177/03946320040170s216] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Previous investigations have shown that Pb exerts immunotoxic effects. Object of this study were Th1 and Th2-type immune responses of mice to Pb exposure. Adult Swiss male mice were administered 0, 40 and 400 mg/1 of Pb (as acetate) in drinking water for 14 days . At the end of the treatment, blood Pb was determined and two Th1 cytokines (IL-2, INF-γ) and one Th2 serum cytokine (IL-4) were measured. A significant increase in IL-4 production was observed in the mice exposed to 40 mg/1 of Pb, while a further increase in IL-4 production was associated with a decrease in IFN-γ production in mice exposed to 400 mg/1 of Pb. On the other hand, Pb exposure did not induce changes of serum IL-2 (involved also in the ThO immune pattern). Our findings indicate that low level Pb exposure enhances a Th2 response. A high Pb dose can either stimulate the Th2 immune activity or reduce the Th1 response; the result is an imbalance between Th1 and Th2 activation.
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Affiliation(s)
- I Iavicoli
- Institute of Occupational Health, Catholic University of Sacred Heart, Rome, Italy
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11
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Nunnari G, Fagone P, Condorelli F, Nicoletti F, Malaguarnera L, Di Rosa M. CD4+ T-cell gene expression of healthy donors, HIV-1 and elite controllers: Immunological chaos. Cytokine 2016; 83:127-135. [PMID: 27108398 DOI: 10.1016/j.cyto.2016.04.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Revised: 03/18/2016] [Accepted: 04/15/2016] [Indexed: 01/20/2023]
Abstract
OBJECTIVES T-cell repertoire dysfunction characterizes human immunodeficiency virus type 1 (HIV-1) infection, but the pathogenic mechanisms remain unclear. Disease progression is probably due to a profound dysregulation of Th1, Th2, Th17 and Treg patterns. The aim of this study was to analyze the features of CD4+ T cells in HIV-positive patients with different viroimmunological profile. METHODS we used a gene expression dataset of CD4+ T cells from healthy donors, HIV+ naive patients and Elite Controllers (EC), obtained from the NCBI Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/, accession number GSE18233). RESULTS Principal Component Analysis (PCA) showed an almost complete overlap between the HIV-infected and EC patients, which cannot easily explain the different responses to HIV infection of these two group of patients. We have found that HIV patients and the EC showed an upregulation of the Th1 pro-inflammatory cytokines and chemokines, compared to the controls. Also, we have surprisingly identified IL28B, which resulted downregulated in HIV and EC compared to healthy controls. We focused attention also on genes involved in the constitution of the immunological synapse and we showed that HLA class I and II genes resulted significantly upregulated in HIV and in EC compared to the control. In addition to it, we have found the upregulation of others syncytial molecules, including LAG3, CTLA4, CD28 and CD3, assisting the formation of syncytia with APC cells. CONCLUSIONS Understanding the mechanisms of HIV-associated immunological chaos is critical to strategically plan focused interventions.
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Affiliation(s)
- G Nunnari
- Unit of Infectious Diseases, Department of Clinical and Molecular Biomedicine, University of Catania, Italy
| | - P Fagone
- Department of Biomedical and Biotechnological Sciences, University of Catania, Italy
| | - F Condorelli
- DiSCAFF & DFB Center, University of Piemonte Orientale A. Avogadro, Novara, Italy
| | - F Nicoletti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Italy
| | - L Malaguarnera
- Department of Biomedical and Biotechnological Sciences, University of Catania, Italy
| | - M Di Rosa
- Department of Biomedical and Biotechnological Sciences, University of Catania, Italy.
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HIV-1 strategies to overcome the immune system by evading and invading innate immune system. HIV & AIDS REVIEW 2016. [DOI: 10.1016/j.hivar.2015.07.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Vassallo M, Moranne O, Ambrosetti D, Jeandel PY, Pomares C, Cassuto E, Boscagli A, Giraud G, Montagne N, Dentone C, Demacina I, Villaggio B, Secondo G, Ferrea G, Passeron C, Saudes L, Kaphan R, Marty P, Rosenthal E. Visceral leishmaniasis due to Leishmania infantum with renal involvement in HIV-infected patients. BMC Infect Dis 2014; 14:561. [PMID: 25358548 PMCID: PMC4216653 DOI: 10.1186/s12879-014-0561-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Accepted: 10/14/2014] [Indexed: 11/12/2022] Open
Abstract
Background We describe histological, clinical findings and outcomes of renal involvement during Leishmania infantum infection in four HIV-infected patients in South France and North Italy hospital settings. Cases presentation Four HIV-infected Caucasian patients (age 24-49) performed renal biopsy during episodes of visceral leishmaniasis. They presented severe immunosuppression, frequent relapses of visceral leishmaniasis during a follow-up period of several years and partial or complete recovery of renal function after anti-parasitic treatment. Main clinical presentations were nephrotic or nephritic syndrome and/or acute renal failure secondary to membranoproliferative type III glomerulonephritis or acute interstitial nephritis. Clinical outcome was poor, probably as a consequence of insufficient immuno-virological control of the HIV infection. Conclusions Our findings suggest that the main histological findings in case of renal involvement due to Leishmania infantum infection in HIV-infected patients are type III MPGN and acute interstitial nephritis, with a histological specificity similar to that observed in canine leishmaniasis. Poor immune status in HIV-infected patients, altering the capacity for parasite clearance, and prolonged course of chronic active VL in this population may lead to the development of specific renal lesions. Electronic supplementary material The online version of this article (doi:10.1186/s12879-014-0561-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Matteo Vassallo
- Department of Internal Medicine, Cannes General Hospital, Cannes, France.
| | - Olivier Moranne
- Department of Nephrology, Dialysis and Transplantation, Nice University Hospital, Nice, France. .,Department of Public Health, Nice University Hospital, Nice, France. .,Laboratory of Human Motricity, Education and Health (LAMHESS), University of Nice Sophia-Antipolis, Nice, France.
| | - Damien Ambrosetti
- Department of Histopathology, Nice University Hospital, Nice, France.
| | | | - Christelle Pomares
- Parasitology and Mycology, Nice University Hospital and Inserm U 1065, Nice-Sophia Antipolis University, Equipe 6, Centre Méditerranéen de Médicine Moléculaire, Nice, France.
| | - Elisabeth Cassuto
- Department of Nephrology, Dialysis and Transplantation, Nice University Hospital, Nice, France.
| | - Annick Boscagli
- Department of Internal Medicine, Cannes General Hospital, Cannes, France.
| | - Guillaume Giraud
- Department of Internal Medicine, Cannes General Hospital, Cannes, France.
| | - Nathalie Montagne
- Department of Internal Medicine, Cannes General Hospital, Cannes, France.
| | - Chiara Dentone
- Department of Infectious Diseases, Sanremo General Hospital, Sanremo, Italy.
| | - Ilaria Demacina
- Department of Infectious Diseases, Sanremo General Hospital, Sanremo, Italy.
| | - Barbara Villaggio
- Department of Histopathology, Genoa University Hospital, Genoa, Italy.
| | - Giovanni Secondo
- Department of Infectious Diseases, Sanremo General Hospital, Sanremo, Italy.
| | - Giuseppe Ferrea
- Department of Infectious Diseases, Sanremo General Hospital, Sanremo, Italy.
| | - Corinne Passeron
- Department of Nephrology, Cannes General Hospital, Cannes, France.
| | - Laurence Saudes
- Department of Internal Medicine, Cannes General Hospital, Cannes, France.
| | - Regis Kaphan
- Department of Internal Medicine, Cannes General Hospital, Cannes, France.
| | - Pierre Marty
- Parasitology and Mycology, Nice University Hospital and Inserm U 1065, Nice-Sophia Antipolis University, Equipe 6, Centre Méditerranéen de Médicine Moléculaire, Nice, France.
| | - Eric Rosenthal
- Department of Internal Medicine, Nice University Hospital, Nice, France.
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Fetal exposure to HIV-1 alters chemokine receptor expression by CD4+T cells and increases susceptibility to HIV-1. Sci Rep 2014; 4:6690. [PMID: 25341640 PMCID: PMC4208038 DOI: 10.1038/srep06690] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Accepted: 09/23/2014] [Indexed: 01/02/2023] Open
Abstract
Absolute numbers of lymphocytes are decreased in uninfected infants born to HIV-1-infected women (HIV-1-exposed). Although the exact mechanism is unknown, fetal exposure to maternal HIV-1-infection could prime the immune system and affect T cell trafficking. We compared the expression of chemokine receptors on cord blood CD4+ T cells from HIV-1-exposed children and healthy controls. At baseline CD4+ T cells had a largely naïve phenotype. However, stimulation with cytokines resulted in an upregulation of inflammatory response-related chemokine receptors on CD4+ T cells, with HIV-1-exposed infants having a significantly higher frequency of CD4+ T cells expressing, in particularly Th2 associated chemokine receptors (CCR3 p < 0.01, CCR8 p = 0.03). Numbers of naive CCR7+ CD4+ T cells were reduced (p = 0.01) in HIV-1-exposed infants. We further assessed whether the inflammatory phenotype was associated with susceptibility to HIV-1 and detected higher levels of p24 upon in in vitro infection of stimulated CD4+ T cells of HIV-1-exposed infants. In summary, fetal exposure to HIV-1 primes the immune system in the infant leading to an enhanced immune activation and altered T cell homing, with potential ramifications regarding T cell responses and the acquisition of HIV-1 as an infant.
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Cytokine/Chemokine responses in activated CD4+ and CD8+ T cells isolated from peripheral blood, bone marrow, and axillary lymph nodes during acute simian immunodeficiency virus infection. J Virol 2014; 88:9442-57. [PMID: 24920807 DOI: 10.1128/jvi.00774-14] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
UNLABELLED Understanding the cytokine/chemokine networks in CD4(+) and CD8(+) T cells during the acute phase of infection is crucial to design therapies for the control of early human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) replication. Here, we measured early changes in CD4(+) and CD8(+) T cells in the peripheral blood (PB), bone marrow (BM), and axillary lymph node (ALN) tissue of rhesus macaques infected with SIVMAC251. At 21 days after infection, all tissues showed a statistically significant loss of CD4(+) T cells along with immune activation of CD8(+) T cells in PB and ALN tissue. Twenty-eight different cytokines/chemokines were quantified in either anti-CD3/28 antibody- or staphylococcal enterotoxin B-stimulated single-positive CD4(+) and CD8(+) T cells. PB CD4(+) T cells produced predominantly interleukin-2 (IL-2), whereas CD4(+) and CD8(+) T-cell subsets in tissues produced β-chemokines both before and 21 days after SIV infection. Tissues generally exhibited massive upregulation of many cytokines/chemokines following infection, possibly in an attempt to mitigate the loss of CD4(+) T cells. There was no evidence of a T-helper 1 (TH1)-to-TH2 shift in CD4(+) T cells or a T-cytotoxic 1 (TC1)-to-TC2 cytokine shift in CD8(+) T cells in PB, BM, and ALN T-cell subsets during the acute phase of SIV infection. Despite the upregulation of several important effector cytokines/chemokines (IL-2, IL-12, IL-17, gamma interferon, granulocyte-macrophage colony-stimulating factor) by CD4(+) and CD8(+) T cells, upregulation of β-chemokines (CCL2 and CCL22), basic fibroblast growth factor (FGF-basic), hepatocyte growth factor (HGF), and migration inhibition factor (MIF) may provide a poor prognosis either by inducing increased virus replication or by other unknown mechanisms. Therefore, drugs targeting β-chemokines (CCL2 and CCL22), FGF-basic, HGF, or MIF might be important for developing effective vaccines and therapeutics against HIV. IMPORTANCE Human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection results in early depletion of CD4(+) T cells and dysregulation of protective immune responses. Therefore, understanding the cytokine/chemokine networks in CD4(+) and CD8(+) T cells in different tissues during the acute phase of infection is crucial to the design of therapies for the control of early viral replication. Here, we measured early changes in CD4(+) and CD8(+) T cells in peripheral blood (PB), bone marrow (BM), and axillary lymph node (ALN) tissue of rhesus macaques infected with SIVMAC251. There was no evidence of a T-helper 1 (TH1)-to-TH2 shift in CD4(+) T cells or a T-cytotoxic 1 (TC1)-to-TC2 cytokine shift in CD8(+) T cells in PB, BM, and ALN T-cell subsets during the acute phase of SIV infection. Despite the upregulation of several important effector cytokines/chemokines by CD4(+) and CD8(+) T cells, upregulation of β-chemokines, fibroblast growth factor-basic, hepatocyte growth factor, and migration inhibition factor may provide a poor prognosis.
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Singh A, Vajpayee M, Ali SA, Chauhan NK. Cellular interplay among Th17, Th1, and Treg cells in HIV-1 subtype "C" infection. J Med Virol 2013; 86:372-84. [PMID: 24249618 DOI: 10.1002/jmv.23810] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/29/2013] [Indexed: 12/28/2022]
Abstract
CD4 T cell depletion is central to HIV pathogenesis and disease progression. Different subsets of CD4 T cells cooperate to combat an infection. Therefore, the immune balance among Th17, Th1, and Treg cells may be critical in HIV immunopathogenesis which is not adequately defined yet. The impact of HIV-1 infection on the interplay of Th17/Th1/Treg cells in HIV-1 infected Indian individuals was examined in the present study and report that HIV-1 Gag specific peripheral blood Th17 cells were significantly depleted in late infected subjects, compared to early infected subjects and slow progressors. Although, the gradual loss of Th1 cells was also reported during HIV-1 disease progression but relative to Th17 cells, Th1 cells were found to be more resistant to HIV-1 infection. Additionally, a significant and progressive gain in Treg cellular frequency was observed as disease progress from early to late stage of HIV-1 infection. This study also indicate that slow progressors might have an intrinsic capacity to develop strong HIV-1 specific Th17 and Th1 cell responses contrasted with a faint Treg cellular performance signifies the importance of these cellular subsets in progressive versus nonprogressive HIV-1 infection. A significant gradual loss of Th17/Treg ratio was found to be associated with disease state, plasma viral load and immune activation.
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Affiliation(s)
- Alpana Singh
- Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India; Saifia College of Science, Barkatullah University, Bhopal, India
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Dynamics of cytokine/chemokine responses in intestinal CD4+ and CD8+ T Cells during Acute Simian Immunodeficiency Virus Infection. J Virol 2013; 87:11916-23. [PMID: 23966391 DOI: 10.1128/jvi.01750-13] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Loss of intestinal CD4(+) T cells was associated with decreased production of several T-helper 1 (TH1) and TH2 cytokines and increased production of interleukin 17 (IL-17), gamma interferon (IFN-γ), CCL4, and granulocyte-macrophage colony-stimulating factor (GM-CSF) by CD8(+) T cells 21 days after simian immunodeficiency virus (SIV) infection in rhesus macaques. Shifting of mucosal TH1 to TH2 or T-cytotoxic 1 (TC1) to TC2 cytokine profiles was not evident. Additionally, both CD4(+) and CD8(+) T cells showed upregulation of macrophage migration inhibition factor (MIF) and basic fibroblast growth factor (FGF-basic) cytokines that have been linked to HIV disease progression.
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18
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Chen W, Huang NT, Oh B, Lam RHW, Fan R, Cornell TT, Shanley TP, Kurabayashi K, Fu J. Surface-micromachined microfiltration membranes for efficient isolation and functional immunophenotyping of subpopulations of immune cells. Adv Healthc Mater 2013; 2:965-975. [PMID: 23335389 DOI: 10.1002/adhm.201200378] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2012] [Indexed: 01/02/2023]
Abstract
An accurate measurement of the immune status in patients with immune system disorders is critical in evaluating the stage of diseases and tailoring drug treatments. The functional cellular immunity test is a promising method to establish the diagnosis of immune dysfunctions. The conventional functional cellular immunity test involves measurements of the capacity of peripheral blood mononuclear cells to produce pro-inflammatory cytokines when stimulated ex vivo. However, this "bulk" assay measures the overall reactivity of a population of lymphocytes and monocytes, making it difficult to pinpoint the phenotype or real identity of the reactive immune cells involved. In this research, we develop a large surface micromachined poly-dimethylsiloxane (PDMS) microfiltration membrane (PMM) with high porosity, which is integrated in a microfluidic microfiltration platform. Using the PMM with functionalized microbeads conjugated with antibodies against specific cell surface proteins, we demonstrated rapid, efficient and high-throughput on-chip isolation, enrichment, and stimulation of subpopulations of immune cells from blood specimens. Furthermore, the PMM-integrated microfiltration platform, coupled with a no-wash homogeneous chemiluminescence assay ("AlphaLISA"), enables us to demonstrate rapid and sensitive on-chip immunophenotyping assays for subpopulations of immune cells isolated directly from minute quantities of blood samples.
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Affiliation(s)
- Weiqiang Chen
- Department of Mechanical Engineering University of Michigan Ann Arbor, MI 48109 USA
| | - Nien-Tsu Huang
- Department of Mechanical Engineering University of Michigan Ann Arbor, MI 48109 USA
| | - Boram Oh
- Department of Mechanical Engineering University of Michigan Ann Arbor, MI 48109 USA
| | - Raymond H W Lam
- Department of Mechanical and Biomedical Engineering City University of Hong Kong, Hong Kong, China
| | - Rong Fan
- Department of Biomedical Engineering Yale University New Haven, CT 06511, USA
| | - Timothy T Cornell
- Department of Pediatrics and Communicable Diseases University of Michigan, Ann Arbor, MI 48109, USA
| | - Thomas P Shanley
- Department of Pediatrics and Communicable Diseases University of Michigan, Ann Arbor, MI 48109, USA
| | - Katsuo Kurabayashi
- Department of Mechanical Engineering University of Michigan Ann Arbor, MI 48109 USA
| | - Jianping Fu
- Department of Mechanical Engineering University of Michigan Ann Arbor, MI 48109 USA
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Tang YW, Graham BS. Potential for Directing Appropriate Responses to Vaccines by Cytokine Manipulation. ACTA ACUST UNITED AC 2012. [DOI: 10.1007/bf03259330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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The breakdown of the cytokine network subsequent to human immunodeficiency virus infection. Mediators Inflamm 2012; 4:315-21. [PMID: 18475658 PMCID: PMC2365659 DOI: 10.1155/s0962935195000512] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
The acquired immunodeflciency syndrome (AIDS) is a clinically multifaceted disease induced by infection with the human immunodeficiency virus (HIV). HIV infection results in a complex pattern of immunologic alterations that leads to the development of AIDS in the majority of HIV seropositive (HIV+) individuals. The reduction in CD4 T lymphocyte counts is the hallmark of HIV infection; nevertheless, long before the reduction in CD4 counts reaches critical levels, a series of profound and complex defects that impair the function of CD4 T lymphocytes can be detected. Thus, HIV infection is characterized by quantitative and qualitative defects affecting CD4 T lymphocytes. It was suggested recently that programmed cell death (PCD) is an important mechanism leading to CD4 depletion in HIV infection, and that susceptibility of peripheral lymphocytes to PCD is differentially regulated by diverse cytokines. Thus, type 1 cytokines would protect CD4 lymphocytes against PCD, whereas type 2 cytokines would not protect against, and could augment, PCD. We suggest that the qualitative alterations of the immune response provoke the CD4 depletion characteristic of HIV disease via type 2 cytokinemediated augmentation of PCD, and are therefore ultimately responsible for the progression of HIV infection. Finally, we summarize recent data showing that three correlates of disease progression: emergence of HIV strains with syncitium-inducing ability (SI), type 1-to-type 2 cytokine shift, and CD4 depletion, are significantly associated, suggesting a complex interconnected virologic-immunologic pathogenesis of HIV infection.
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Li Y, Ling W, Xu H, Wang M, Wu C. The activation and dynamics of cytokine expression by CD4+ T cells and AIDS progression in HIV-1-infected Chinese individuals. Microb Pathog 2012; 53:189-97. [PMID: 22892467 DOI: 10.1016/j.micpath.2012.07.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2012] [Revised: 06/28/2012] [Accepted: 07/25/2012] [Indexed: 11/17/2022]
Abstract
CD4(+) T cells are the main targets of HIV-1 and play a central role during the progression of AIDS, but the mechanism has not been clearly elucidated. In the present study, blood samples were collected from HIV-1-infected Chinese individuals, including typical progressors (TPs) and long-term nonprogressors (LTNPs). More HIV-1 productively infected CD4(+) T cells were obtained through co-cultures and the infected CD4(+) T cells were discriminated from bystander cells by intracellular p24 staining. The activation level and dynamics of cytokine expression of CD4(+) T cells were analyzed. After stimulating the freshly isolated PBMCs with PHA, the frequencies of CD69(+)CD4(+) T cells/CD25(+)CD4(+) T cells were higher in TP than in LTNP group and were positively correlated with viral load and negatively correlated with CD4(+) T cell counts. The activation level of CD4(+) T cells in the co-cultured PBMCs was higher in TP than in LTNP group, and HIV-1 productively infected CD4(+) T cells were more activated than bystander CD4(+) T cells. The expression of Th1 cytokines (IL-2 and IFN-γ) and the frequency of Th1 cells in co-cultured PBMCs were lower in TP than in LTNP group. HIV-1 productively infected CD4(+) T cells expressed higher level of Th1/Th2 cytokines than bystander cells. More productive HIV-1 infection occurred in Th1 than in Th2 cells, followed by Th0 cells. The present results suggest that the excessive activation level of CD4(+) T cells and the preferential replication of HIV-1 in Th1 cells that lead to the shift of Th1 to Th2 are likely crucial to AIDS progression in HIV-1-infected Chinese individuals.
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Affiliation(s)
- Yan Li
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, PR China
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Kang W, Li Y, Zhuang Y, Zhao K, Huang D, Sun Y. Dynamic analysis of Th1/Th2 cytokine concentration during antiretroviral therapy of HIV-1/HCV co-infected patients. BMC Infect Dis 2012; 12:102. [PMID: 22533731 PMCID: PMC3353863 DOI: 10.1186/1471-2334-12-102] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2011] [Accepted: 04/25/2012] [Indexed: 12/30/2022] Open
Abstract
Background Co-infection with hepatitis C (HCV) is very common in human immunodeficiency virus 1 (HIV-1) infected patients. Although HIV co-infection clearly accelerates progression of HCV-related fibrosis and liver disease, controversy remains as to the impact of HCV on HIV disease progression in co-infected patients. HIV can cause immune dysfunction, in which the regulatory function of T helper (Th) cells is very essential. Moreover, cytokines derived from Th cells play a prominent role in viral infection. Investigating the functional changes of Th1 and Th2 cells in cytokine level can improve the understanding of the effect of co-infected HCV on HIV infection. Methods In this study, we measured the baseline Th1/Th2 cytokine concentration in sera by using flow cytometry in HIV/HCV co-infection, HIV mono-infection, HCV mono-infection, and healthy control group, as well as the dynamic changes of these cytokine levels after receiving highly active antiretroviral therapy (HAART). Results The ratio of Th1 and Th2 cytokine concentration in HIV/HCV co-infection was higher than HCV mono-infection and healthy control group, while lower than HIV mono-infection group. After HAART was initiated, the Th1/Th2 ratio of HIV/HCV co-infection group decreased to the same level of healthy control, while HIV mono-infection group was still higher than the control group. Conclusions There was no significant evidence showing co-infected with HCV had negative effect on HIV related diseases. However, co-infected with HCV can decrease Th1/Th2 ratio by affecting Th1 cytokine level, especially the secretion of IFN-γ. With the initiation of HAART, Th1 and Th2 cytokine levels were progressively reduced. HIV was the main stimulating factor of T cells in HIV/HCV co-infection group.
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Affiliation(s)
- Wenzhen Kang
- Department of Infectious Diseases, Tangdu Hospital Affiliated to the Fourth Military Medical University, Xi'an, P.R. China.
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Boga JA, Coto-Montes A, Rosales-Corral SA, Tan DX, Reiter RJ. Beneficial actions of melatonin in the management of viral infections: a new use for this "molecular handyman"? Rev Med Virol 2012; 22:323-38. [PMID: 22511571 PMCID: PMC7169144 DOI: 10.1002/rmv.1714] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2011] [Revised: 02/08/2012] [Accepted: 02/09/2012] [Indexed: 12/24/2022]
Abstract
Melatonin (N‐acetyl‐5‐methoxytryptamine) is a multifunctional signaling molecule that has a variety of important functions. Numerous clinical trials have examined the therapeutic usefulness of melatonin in different fields of medicine. Clinical trials have shown that melatonin is efficient in preventing cell damage under acute (sepsis, asphyxia in newborns) and chronic states (metabolic and neurodegenerative diseases, cancer, inflammation, aging). The beneficial effects of melatonin can be explained by its properties as a potent antioxidant and antioxidant enzyme inducer, a regulator of apoptosis and a stimulator of immune functions. These effects support the use of melatonin in viral infections, which are often associated with inflammatory injury and increases in oxidative stress. In fact, melatonin has been used recently to treat several viral infections, which are summarized in this review. The role of melatonin in infections is also discussed herein. Copyright © 2012 John Wiley & Sons, Ltd.
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Affiliation(s)
- Jose Antonio Boga
- Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, Texas, USA
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Kynyk JA, Parsons JP, Para MF, Koletar SL, Diaz PT, Mastronarde JG. HIV and asthma, is there an association? Respir Med 2012; 106:493-9. [PMID: 22285768 PMCID: PMC4235227 DOI: 10.1016/j.rmed.2011.12.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2011] [Revised: 11/13/2011] [Accepted: 12/28/2011] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To evaluate whether asthma and airway hyper-responsiveness are associated with HIV infection. METHODS We reviewed the literature on HIV-associated pulmonary diseases, pulmonary symptoms, and immune changes which may play a role in asthma. The information was analyzed comparing the pre-HAART era to the post-HAART era data. RESULTS HIV-seropositive individuals commonly experience respiratory complaints yet it is unclear if the frequency of these complaints have changed with the initiation of HAART. Changes in pulmonary function testing and serum IgE are seen with HIV infection even in the post-HAART era. An increased prevalence of asthma among HIV-seropositive children treated with HAART has been reported. CONCLUSION The spectrum of HIV-associated pulmonary disease has changed with the introduction of HAART. Current data is limited to determine if asthma and airway hyper-responsiveness are more common among HIV-seropositive individuals treated with HAART.
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Affiliation(s)
- Jessica A Kynyk
- The Ohio State University, Department of Internal Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, 201 Davis Heart & Lung Research Institute, 473 West 12th Avenue, Columbus, OH 43210, USA.
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Simonetta F, Lecuroux C, Girault I, Goujard C, Sinet M, Lambotte O, Venet A, Bourgeois C. Early and long-lasting alteration of effector CD45RA(-)Foxp3(high) regulatory T-cell homeostasis during HIV infection. J Infect Dis 2012; 205:1510-9. [PMID: 22457280 DOI: 10.1093/infdis/jis235] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Regulatory T-cell (Treg) quantification in human immunodeficiency virus (HIV) infection remains ill defined because of the lack of reliable specific markers to identify human Tregs and the diversity of clinical stages of HIV infection. Using a recently described Treg identification strategy based on CD45RA and Foxp3 expression, we performed an extensive quantification of total, naive (CD45RA(+)Foxp3(low)), and effector (CD45RA(-)Foxp3(high)) Tregs in different contexts of HIV infection: primary HIV infection, long-term viremic patients, aviremic patients treated with highly active antiretroviral therapy, and HIV controllers. We showed that although total Treg percentages were mildly affected by HIV infection, Treg absolute numbers were significantly reduced in all groups studied. We demonstrated that although naive Treg numbers were essentially preserved, effector Tregs were consistently affected during HIV infection. Finally, we demonstrated that effector but not total or naive Treg numbers were negatively correlated with the magnitude of HIV-specific CD8 T-cell responses.
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Ahmed Z, Czubala M, Blanchet F, Piguet V. HIV impairment of immune responses in dendritic cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2012; 762:201-38. [PMID: 22975877 DOI: 10.1007/978-1-4614-4433-6_8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
Abstract
Dendritic cells and their subsets are diverse populations of immune cells in the skin and mucous membranes that possess the ability to sense the presence of microbes and orchestrate an efficient and adapted immune response. Dendritic cells (DC) have the unique ability to act as a bridge between the innate and adaptive immune responses. These cells are composed of a number of subsets behaving with preferential and specific features depending on their location and surrounding environment. Langerhans cells (LC) or dermal DC (dDC) are readily present in mucosal areas. Other DC subsets such as plasmacytoid DC (pDC), myeloid DC (myDC), or monocyte-derived DC (MDDC) are thought to be recruited or differentiated in sites of pathogenic challenge. Upon HIV infection, DC and their subsets are likely among the very first immune cells to encounter incoming pathogens and initiate innate and adaptive immune responses. However, as evidenced during HIV infection, some pathogens have evolved subtle strategies to hijack key cellular machineries essential to generate efficient antiviral responses and subvert immune responses for spread and survival.In this chapter, we review recent research aimed at investigating the involvement of DC subtypes in HIV transmission at mucosal sites, concentrating on HIV impact on cellular signalling and trafficking pathways in DC leading to DC-mediated immune response alterations and viral immune evasion. We also address some aspects of DC functions during the chronic immune pathogenesis and conclude with an overview of the current and novel therapeutic and prophylactic strategies aimed at improving DC-mediated immune responses, thus to potentially tackle the early events of mucosal HIV infection and spread.
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Affiliation(s)
- Zahra Ahmed
- Department of Dermatology and Wound Healing, Cardiff University School of Medicine, Cardiff, Wales, UK
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28
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Guerra C, Morris D, Sipin A, Kung S, Franklin M, Gray D, Tanzil M, Guilford F, Khasawneh FT, Venketaraman V. Glutathione and adaptive immune responses against Mycobacterium tuberculosis infection in healthy and HIV infected individuals. PLoS One 2011; 6:e28378. [PMID: 22164280 PMCID: PMC3229597 DOI: 10.1371/journal.pone.0028378] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2011] [Accepted: 11/07/2011] [Indexed: 11/18/2022] Open
Abstract
Glutathione (GSH), a tripeptide antioxidant, is essential for cellular homeostasis and plays a vital role in diverse cellular functions. Individuals who are infected with Human immuno deficiency virus (HIV) are known to be susceptible to Mycobacterium tuberculosis (M. tb) infection. We report that by enhancing GSH levels, T-cells are able to inhibit the growth of M. tb inside macrophages. In addition, those GSH-replenished T cell cultures produced increased levels of Interleukin-2 (IL-2), Interleukin-12 (IL-12), and Interferon-gamma (IFN-γ), cytokines, which are known to be crucial for the control of intracellular pathogens. Our study reveals that T lymphocytes that are derived from HIV infected individuals are deficient in GSH, and that this deficiency correlates with decreased levels of Th1 cytokines and enhanced growth of M. tb inside human macrophages.
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Affiliation(s)
- Carlos Guerra
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, United States of America
| | - Devin Morris
- Graduate of College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, United States of America
| | - Andrea Sipin
- California State Polytechnic University, Pomona, California, United States of America
| | - Steven Kung
- California State Polytechnic University, Pomona, California, United States of America
| | - Mesharee Franklin
- Graduate of College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, United States of America
| | - Dennis Gray
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, United States of America
- Graduate of College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, United States of America
| | - Michelle Tanzil
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, United States of America
- Graduate of College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, United States of America
| | | | - Fadi T. Khasawneh
- College of Pharmacy, Western University of Health Sciences, Pomona, California, United States of America
| | - Vishwanath Venketaraman
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, United States of America
- Graduate of College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, United States of America
- * E-mail:
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Liu Y, Yan J, Howland MC, Kwa T, Revzin A. Micropatterned aptasensors for continuous monitoring of cytokine release from human leukocytes. Anal Chem 2011; 83:8286-92. [PMID: 21942846 PMCID: PMC3235337 DOI: 10.1021/ac202117g] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
We report the development of a microdevice for detecting local interferon gamma (IFN-γ) release from primary human leukocytes in real time. Our microdevice makes use of miniature aptamer-modified electrodes integrated with microfluidics to monitor cellular production of IFN-γ. The aptamer species consists of a DNA hairpin molecule with thiol groups on the 3'-end for self-assembly onto Au electrodes. A redox reporter is covalently attached at the 5'-end for electrochemical sensing. This aptasensor has excellent sensitivity for IFN-γ (<60 pM detection limit) and responds to the target analyte in real time without additional washing or labeling steps. Aptamer-functionalized electrode arrays are fabricated on glass slides containing poly(ethylene glycol) (PEG) hydrogel patterns designed to expose glass regions adjacent to electrodes while protecting the remainder of the surface from nonspecific adsorption. The micropatterned substrates are integrated with PDMS microfluidic channels and incubated with T-cell-specific antibodies (Ab) (anti-CD4). Upon injection of blood, leukocytes are bound to Ab-modified glass regions in proximity to aptasensors. Cytokine release from captured cells is triggered by mitogenic activation and detected at the aptamer-modified electrodes using square wave voltammetry (SWV). The IFN-γ signal is monitored in real time with signal appearing as early as 15 min poststimulation from as few as 90 T cells. The observed IFN-γ release profiles are used to calculate an initial IFN-γ production rate of 0.0079 pg cell(-1) h(-1) upon activation. The work described here represents an important step toward development of aptasensors for immune cell analysis and blood-based diagnostics.
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Affiliation(s)
- Ying Liu
- Department of Biomedical Engineering, University of California, Davis, CA, 95616, United States
| | - Jun Yan
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, United States
| | - Michael C. Howland
- Department of Biomedical Engineering, University of California, Davis, CA, 95616, United States
| | - Timothy Kwa
- Department of Biomedical Engineering, University of California, Davis, CA, 95616, United States
| | - Alexander Revzin
- Department of Biomedical Engineering, University of California, Davis, CA, 95616, United States
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Gulzar N, Diker B, Balasubramanian S, Jiang JQ, Copeland KF. Human immunodeficiency virus-1 infection protects against a Tc1-to-Tc2 shift in CD8+ T cells. Hum Immunol 2011; 72:995-1000. [DOI: 10.1016/j.humimm.2011.08.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2011] [Revised: 08/11/2011] [Accepted: 08/25/2011] [Indexed: 12/11/2022]
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Wu JQ, Dwyer DE, Dyer WB, Yang YH, Wang B, Saksena NK. Genome-wide analysis of primary CD4+ and CD8+ T cell transcriptomes shows evidence for a network of enriched pathways associated with HIV disease. Retrovirology 2011; 8:18. [PMID: 21410942 PMCID: PMC3068086 DOI: 10.1186/1742-4690-8-18] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2010] [Accepted: 03/16/2011] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND HIV preferentially infects CD4+ T cells, and the functional impairment and numerical decline of CD4+ and CD8+ T cells characterize HIV disease. The numerical decline of CD4+ and CD8+ T cells affects the optimal ratio between the two cell types necessary for immune regulation. Therefore, this work aimed to define the genomic basis of HIV interactions with the cellular transcriptome of both CD4+ and CD8+ T cells. RESULTS Genome-wide transcriptomes of primary CD4+ and CD8+ T cells from HIV+ patients were analyzed at different stages of HIV disease using Illumina microarray. For each cell subset, pairwise comparisons were performed and differentially expressed (DE) genes were identified (fold change >2 and B-statistic >0) followed by quantitative PCR validation. Gene ontology (GO) analysis of DE genes revealed enriched categories of complement activation, actin filament, proteasome core and proton-transporting ATPase complex. By gene set enrichment analysis (GSEA), a network of enriched pathways functionally connected by mitochondria was identified in both T cell subsets as a transcriptional signature of HIV disease progression. These pathways ranged from metabolism and energy production (TCA cycle and OXPHOS) to mitochondria meditated cell apoptosis and cell cycle dysregulation. The most unique and significant feature of our work was that the non-progressing status in HIV+ long-term non-progressors was associated with MAPK, WNT, and AKT pathways contributing to cell survival and anti-viral responses. CONCLUSIONS These data offer new comparative insights into HIV disease progression from the aspect of HIV-host interactions at the transcriptomic level, which will facilitate the understanding of the genetic basis of transcriptomic interaction of HIV in vivo and how HIV subverts the human gene machinery at the individual cell type level.
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Affiliation(s)
- Jing Qin Wu
- Retroviral Genetics Division, Center for Virus Research, Westmead Millennium Institute, University of Sydney, Darcy Road, Westmead, NSW 2145, Australia
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Watanabe D, Uehira T, Yonemoto H, Bando H, Ogawa Y, Yajima K, Taniguchi T, Kasai D, Nishida Y, Shirasaka T. Sustained high levels of serum interferon-γ during HIV-1 infection: a specific trend different from other cytokines. Viral Immunol 2011; 23:619-25. [PMID: 21142447 DOI: 10.1089/vim.2010.0065] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The expression levels of various cytokines increase with the progression of HIV-1 infection. However, the effects of antiretroviral therapy (ART) on serum cytokine levels have not been fully determined. In this study we measured serum cytokine levels of 35 HIV-1-infected Japanese adults. We first performed a cross-sectional study and observed that TNF-α, IL-6, IL-10, IL-18, and IL-7 levels all showed significant increases in those with advanced disease, and that this had a significant negative correlation with the CD4 cell count. However, IFN-γ levels did not show this relationship. A longitudinal study in 18 HIV-1-infected patients with a CD4 cell count <350/μL revealed that the introduction of ART reduced cytokine levels. Significant reductions of IL-7, IL-10, IFN-γ, and IL-18 levels were observed on days 30, 60, 90, and 90 after the initiation of ART, respectively. These results indicate a discrepancy between cross-sectional and longitudinal studies of serum levels of IFN-γ. To clarify this, we investigated serum IFN-γ levels in each patient. In 5 of the 15 patients IFN-γ levels did not decrease, even after ART initiation, and remained at 5 pg/mL or higher on day 120 after ART initiation. Higher IFN-γ levels (>5 pg/mL) were also observed in 2 of 7 asymptomatic patients, and 2 of 11 patients who underwent ART for 1 year or longer. These data demonstrate that IFN-γ levels in some patients increased and remained high even after the initiation of ART, which was a specific observation different from those of the other cytokines.
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Affiliation(s)
- Dai Watanabe
- AIDS Medical Center, Osaka National Hospital, National Hospital Organization, Osaka City, Osaka, Japan
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Stybayeva G, Mudanyali O, Seo S, Silangcruz J, Macal M, Ramanculov E, Dandekar S, Erlinger A, Ozcan A, Revzin A. Lensfree holographic imaging of antibody microarrays for high-throughput detection of leukocyte numbers and function. Anal Chem 2010; 82:3736-44. [PMID: 20359168 PMCID: PMC2864520 DOI: 10.1021/ac100142a] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Characterization of leukocytes is an integral part of blood analysis and blood-based diagnostics. In the present paper, we combine lensless holographic imaging with antibody microarrays for rapid and multiparametric analysis of leukocytes from human blood. Monoclonal antibodies (Abs) specific for leukocyte surface antigens (CD4 and CD8) and cytokines (TNF-alpha, IFN-gamma, IL-2) were printed in an array so as to juxtapose cell capture and cytokine detection antibody (Ab) spots. Integration of Ab microarrays into a microfluidic flow chamber (4 muL volume) followed by incubation with human blood resulted in capture of CD4 and CD8 T-cells on specific Ab spots. On-chip mitogenic activation of these cells induced release of cytokine molecules that were subsequently captured on neighboring anticytokine Ab spots. The binding of IL-2, TNF-alpha, and IFN-gamma molecules on their respective Ab spots was detected using horseradish peroxidase (HRP)-labeled anticytokine Abs and a visible color reagent. Lensfree holographic imaging was then used to rapidly ( approximately 4 s) enumerate CD4 and CD8 T-lymphocytes captured on Ab spots and to quantify the cytokine signal emanating from IL-2, TNF-alpha, and IFN-gamma spots on the same chip. To demonstrate the utility of our approach for infectious disease monitoring, blood samples of healthy volunteers and human immunodeficiency virus (HIV)-infected patients were analyzed to determine the CD4/CD8 ratio, an important HIV/AIDS diagnostic marker. The ratio obtained by lensfree on-chip imaging of CD4 and CD8 T-cells captured on Ab spots was in close agreement with conventional microscopy-based cell counting. The present paper, describing tandem use of Ab microarrays and lensfree holographic imaging, paves the way for future development of miniature cytometry devices for multiparametric blood analysis at the point of care or in a resource-limited setting.
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Affiliation(s)
- Gulnaz Stybayeva
- Department of Biomedical Engineering, University of California, Davis
| | - Onur Mudanyali
- Department of Electrical Engineering, University of California, Los Angeles
| | - Sungkyu Seo
- Department of Electrical Engineering, University of California, Los Angeles
- Dept. of Electronics and Information Engineering, Korea University, Korea
| | - Jaime Silangcruz
- Department of Electrical Engineering, University of California, Los Angeles
| | - Monica Macal
- Department of Medical Microbiology and Immunology, University of California, Davis
| | - Erlan Ramanculov
- National Center for Biotechnology, Astana, Republic of Kazakhstan
| | - Satya Dandekar
- Department of Medical Microbiology and Immunology, University of California, Davis
| | - Anthony Erlinger
- Department of Electrical Engineering, University of California, Los Angeles
| | - Aydogan Ozcan
- Department of Electrical Engineering, University of California, Los Angeles
- California NanoSystems Institute, University of California, Los Angeles
| | - Alexander Revzin
- Department of Biomedical Engineering, University of California, Davis
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Maksaereekul S, Dubie RA, Shen X, Kieu H, Dean GA, Sparger EE. Vaccination with vif-deleted feline immunodeficiency virus provirus, GM-CSF, and TNF-alpha plasmids preserves global CD4 T lymphocyte function after challenge with FIV. Vaccine 2009; 27:3754-65. [PMID: 19464559 PMCID: PMC2802579 DOI: 10.1016/j.vaccine.2009.03.081] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2008] [Revised: 03/24/2009] [Accepted: 03/26/2009] [Indexed: 12/17/2022]
Abstract
Feline immunodeficiency virus (FIV) DNA vaccine approaches that included a vif-deleted FIV provirus (FIV-pPPRDeltavif) and feline cytokine expression plasmids were tested for immunogenicity and efficacy by immunization of specific pathogen free cats. Vaccine protocols included FIV-pPPRDeltavif plasmid alone; a combination of FIV-pPPRDeltavif DNA and feline granulocyte macrophage-colony stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-alpha expression plasmids; or a combination of FIV-pPPRDeltavif and feline interleukin (IL)-15 plasmids. Cats immunized with FIV-pPPRDeltavif, GM-CSF and TNF-alpha plasmids demonstrated an increased frequency of FIV-specific T cell proliferation responses compared to other vaccine groups. Immunization with FIV-pPPRDeltavif and IL-15 plasmids was distinguished from other vaccine protocols by the induction of antiviral antibodies. Suppression of virus loads was not observed for any of the FIV-pPPRDeltavif DNA vaccine protocols after challenge with the FIV-PPR isolate. However, prior immunization with FIV-pPPRDeltavif, GM-CSF, and TNF-alpha plasmids resulted in preservation of CD4 T cell functions, including mitogen-induced cytokine expression and antigen-specific proliferation upon infection with FIV. These findings justify further examination of cytokine combinations as adjuvants for lentiviral DNA vaccines.
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Affiliation(s)
- Saipiroon Maksaereekul
- Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, California 95616
| | - Robert A. Dubie
- Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, California 95616
| | - Xiaoying Shen
- Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, California 95616
| | - Hung Kieu
- Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, California 95616
| | - Gregg A. Dean
- Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606
| | - Ellen E. Sparger
- Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, California 95616
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35
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IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells. Blood 2009; 114:346-56. [PMID: 19365081 DOI: 10.1182/blood-2008-12-191296] [Citation(s) in RCA: 224] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Murine models indicate that interleukin-10 (IL-10) can suppress viral clearance, and interventional blockade of IL-10 activity has been proposed to enhance immunity in chronic viral infections. Increased IL-10 levels have been observed during HIV infection and IL-10 blockade has been shown to enhance T-cell function in some HIV-infected subjects. However, the categories of individuals in whom the IL-10 pathway is up-regulated are poorly defined, and the cellular sources of IL-10 in these subjects remain to be determined. Here we report that blockade of the IL-10 pathway augmented in vitro proliferative capacity of HIV-specific CD4 and CD8 T cells in individuals with ongoing viral replication. IL-10 blockade also increased cytokine secretion by HIV-specific CD4 T cells. Spontaneous IL-10 expression, measured as either plasma IL-10 protein or IL-10 mRNA in peripheral blood mononuclear cells (PBMCs), correlated positively with viral load and diminished after successful antiretroviral therapy. IL-10 mRNA levels were up-regulated in multiple PBMC subsets in HIV-infected subjects compared with HIV-negative controls, particularly in T, B, and natural killer (NK) cells, whereas monocytes were a major source of IL-10 mRNA in HIV-infected and -uninfected individuals. These data indicate that multiple cell types contribute to IL-10-mediated immune suppression in the presence of uncontrolled HIV viremia.
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36
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Zhu H, Stybayeva G, Macal M, Ramanculov E, George MD, Dandekar S, Revzin A. A microdevice for multiplexed detection of T-cell-secreted cytokines. LAB ON A CHIP 2008; 8:2197-205. [PMID: 19023487 DOI: 10.1039/b810244a] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Cytokines are produced by immune cells in response to viral or bacterial pathogens and therefore have significant diagnostic value. The goal of the present study was to develop a miniature device for detection of interleukin (IL)-2 and interferon (IFN)-gamma cytokines secreted by a small population of CD4 and CD8 T-cells. Microarrays of T-cell- and cytokine-specific Ab spots were printed onto poly(ethylene glycol) (PEG) hydrogel-coated glass slides and enclosed inside a microfluidic device, creating a miniature ( approximately 3 microL) immunoreaction chamber. Introduction of the red blood cell (RBC) depleted whole human blood into the microfluidic device followed by washing at a pre-defined shear stress resulted in isolation of pure CD4 and CD8 T-cells on their respective Ab spots. Importantly, the cells became localized next to anti-IL-2 and -IFN-gamma Ab spots. Mitogenic activation of the captured T-cells was followed by immunofluorescent staining (all steps carried out inside a microfluidic device), revealing concentration gradients of surface-bound cytokine molecules. A microarray scanner was then used to quantify the concentration of IFN-gamma and IL-2 near CD4 and CD8 T-cells. This study represents one of the first demonstrations of a microdevice for capturing desired T-cell subsets from a small blood volume and determining, on-chip, cytokine profiles of the isolated cells. Such a microdevice is envisioned as an immunology tool for multi-parametric analysis of T-cell function with direct applications in diagnosis/monitoring of HIV and other infectious diseases.
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Affiliation(s)
- He Zhu
- Department of Biomedical Engineering, University of California, Davis, 451 East Health Sciences St. #2619, Davis, CA 95616, USA
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37
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Sirskyj D, Thèze J, Kumar A, Kryworuchko M. Disruption of the gamma c cytokine network in T cells during HIV infection. Cytokine 2008; 43:1-14. [PMID: 18417356 DOI: 10.1016/j.cyto.2008.03.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2007] [Revised: 02/05/2008] [Accepted: 03/03/2008] [Indexed: 01/03/2023]
Abstract
The common gamma chain (gammac)-sharing cytokines (IL's-2, 4, 7, 9, 15, and 21) play a vital role in the survival, proliferation, differentiation and function of T lymphocytes. As such, disruption of their signaling pathways would be expected to have severe consequences on the integrity of the immune system. Indeed, it appears that the signaling network of these cytokines is both disrupted and exploited by HIV at various stages of infection. IL-2 secretion and signaling downstream of its receptor are impaired in T cells from chronically-infected HIV+ patients. Elevated plasma IL-7 levels and decreased IL-7Ralpha expression in patient T cells results in significantly decreased responsiveness to this critical cytokine. Interestingly, IL-2 and IL-15 are also able to render CD4+ T cells permissive to HIV infection through their influence on the activity of the APOBEC3G deaminase enzyme. Herein, we describe the current state of knowledge on how the gammac cytokine network is affected during HIV infection, with a focus on how this impairs CD4+ and CD8+ T cell function while also benefiting the virus itself. We also address the use of cytokines as adjuncts to highly active antiretroviral therapy to bolster immune reconstitution in infected patients.
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Affiliation(s)
- Danylo Sirskyj
- Infectious Disease and Vaccine Research Centre, Children's Hospital of Eastern Ontario (CHEO)-Research Institute, Ottawa, Ontario, Canada
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38
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Dhillon NK, Williams R, Peng F, Tsai YJ, Dhillon S, Nicolay B, Gadgil M, Kumar A, Buch SJ. Cocaine-mediated enhancement of virus replication in macrophages: implications for human immunodeficiency virus-associated dementia. J Neurovirol 2008; 13:483-95. [PMID: 18097880 DOI: 10.1080/13550280701528684] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Injection drug use has been recognized as a major risk factor for acquired immunodeficiency syndrome (AIDS) from the outset of the epidemic. Cocaine, one of the most widely abused drugs in the United States, can both impair the functions of macrophages and CD4(+) lymphocytes and also activate human immunodeficiency virus (HIV)-1 expression in these cells. Because the brain is the target organ for both cocaine and HIV, the objective of the present study was to explore the effects of cocaine on virus replication in macrophages, the target cells for the virus in the central nervous system (CNS). Cocaine markedly enhanced virus production in simian human immunodeficiency virus (SHIV)-infected monocyte-derived macrophages (MDMs) and in U1 cells, a chronically infected promonocytic cell line as monitored by enzyme-linked immunosorbent assay (ELISA) and immunocytochemistry. Cocaine treatment also resulted in the activation of nuclear factor (NF)-kappa B and transcriptional activation of the HIV-LTR (long terminal repeat) gag-GFP (green fluorescent protein). Analyses of chemokines in cocaine-treated macrophages by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Luminex assays suggested increased expression of interleukin (IL)-10, a cytokine that is known to promote HIV replication in MDMs. In addition to enhancing IL-10 expression, cocaine also caused an up-regulation of the macrophage activation marker, human leukocyte antigen (HLA)-DR, in MDMs. The synergistic effect of cocaine on virus replication and its enhancement of host activation markers suggest that cocaine functions at multiple pathways to accelerate HIV-associated dementia (HAD).
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Affiliation(s)
- Navneet K Dhillon
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
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39
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Emilie D, Galanaud P. Section Review Biologicals & Immunologicals: Deregulation of cytokine production in AIDS: implication for therapy. Expert Opin Investig Drugs 2008. [DOI: 10.1517/13543784.4.10.997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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40
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Vultaggio A, Lombardelli L, Giudizi MG, Biagiotti R, Mazzinghi B, Scaletti C, Mazzetti M, Livi C, Leoncini F, Romagnani S, Maggi E, Piccinni MP. T cells specific for Candida albicans antigens and producing type 2 cytokines in lesional mucosa of untreated HIV-infected patients with pseudomembranous oropharyngeal candidiasis. Microbes Infect 2008; 10:166-74. [DOI: 10.1016/j.micinf.2007.11.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2007] [Revised: 10/31/2007] [Accepted: 11/07/2007] [Indexed: 10/22/2022]
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41
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Gamma/Delta T-cell functional responses differ after pathogenic human immunodeficiency virus and nonpathogenic simian immunodeficiency virus infections. J Virol 2007; 82:1155-65. [PMID: 18045946 DOI: 10.1128/jvi.01275-07] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The objective of this study was to functionally assess gamma/delta (gammadelta) T cells following pathogenic human immunodeficiency virus (HIV) infection of humans and nonpathogenic simian immunodeficiency virus (SIV) infection of sooty mangabeys. gammadelta T cells were obtained from peripheral blood samples from patients and sooty mangabeys that exhibited either a CD4-healthy (>200 CD4(+) T cells/mul blood) or CD4-low (<200 CD4 cells/mul blood) phenotype. Cytokine flow cytometry was utilized to assess production of Th1 cytokines tumor necrosis factor alpha and gamma interferon following ex vivo stimulation with either phorbol myristate acetate/ionomycin or the Vdelta2 gammadelta T-cell receptor agonist isopentenyl pyrophosphate. Sooty mangabeys were observed to have higher percentages of gammadelta T cells in their peripheral blood than humans did. Following stimulation, gammadelta T cells from SIV-positive (SIV(+)) mangabeys maintained or increased their ability to express the Th1 cytokines regardless of CD4(+) T-cell levels. In contrast, HIV-positive (HIV(+)) patients exhibited a decreased percentage of gammadelta T cells expressing Th1 cytokines following stimulation. This dysfunction is primarily within the Vdelta2(+) gammadelta T-cell subset which incurred both a decreased overall level in the blood and a reduced Th1 cytokine production. Patients treated with highly active antiretroviral therapy exhibited a partial restoration in their gammadelta T-cell Th1 cytokine response that was intermediate between the responses of the uninfected and HIV(+) patients. The SIV(+) sooty mangabey natural hosts, which do not proceed to clinical AIDS, provide evidence that gammadelta T-cell dysfunction occurs in HIV(+) patients and may contribute to HIV disease progression.
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Shearer GM, Clerici M, Sarin A, Berzofsky JA, Henkart PA. Cytokines in immune regulation/pathogenesis in HIV infection. CIBA FOUNDATION SYMPOSIUM 2007; 195:142-7; discussion 147-53. [PMID: 8724835 DOI: 10.1002/9780470514849.ch10] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Two hallmarks of immunopathogenesis in the progression of HIV-infected individuals to AIDS are the loss of T helper (Th) cell function in response to antigens and the critical reduction in CD4+ T cell numbers. It is probable that these two phenomena are related. We observed that: (1) the failure to detect antigen-stimulated Th cell responses in vitro correlates with increased pokeweed mitogen/staphylococcal enterotoxin B (P/S)-stimulated and antigen-stimulated T cell death; and (2) both of these events are similarly modulated by immunoregulatory cytokines. Interleukin 2 (IL-2) and IL-12 (Th1-type cytokines), as well as antibodies to IL-4 and IL-10 (which are Th2-type cytokines) restore in vitro Th cell responses to recall antigens such as influenza virus and HIV envelope synthetic peptides (env). P/S-induced T cell death affects both CD4+ and CD8+ T cell subsets, whereas death induced by stimulation with env affects only CD4+ T cells. In both examples, Th1-type cytokines and antibodies to Th2-type cytokines protect against T cell death. In contrast, IL-4 and IL-10 do not protect against death, and anti-IL-12 antibody can enhance T cell death. Our findings indicate that the loss of Th cell function and increased T cell death seen in vitro are correlated, and that in vivo HIV infection gives rise to inappropriate cytokines resulting in immune dysfunction and immunopathogenesis.
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Affiliation(s)
- G M Shearer
- National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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43
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Mayol K, Munier S, Beck A, Verrier B, Guillon C. Design and characterization of an HIV-1 Tat mutant: Inactivation of viral and cellular functions but not antigenicity. Vaccine 2007; 25:6047-60. [PMID: 17604883 DOI: 10.1016/j.vaccine.2007.05.048] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2006] [Revised: 04/02/2007] [Accepted: 05/13/2007] [Indexed: 11/19/2022]
Abstract
Among HIV-1 proteins, Tat is a promising antigen for consideration as a component of anti-HIV-1 vaccine formulations. Nevertheless, this viral protein is able to affect the expression of several cellular genes that are implicated in immune response. In this study, we designed and characterized a mutant form of Tat ("STLA Tat"), which is unable to transactivate viral transcription, and which has lost the deleterious effects on the expression of MHC I, IL-2, and CD25 genes compared with wild-type Tat, as observed in lymphoid Jurkat cells that stably express the tat genes. In vivo experiments in mice revealed that STLA Tat induces anti-Tat antibodies at the same titers as wild-type Tat, which recognize both autologous and heterologous Tat antigens. Finally, STLA Tat did not induce the immunosuppression observed after injection of wild-type Tat. Therefore, this STLA Tat mutant appears to be a safe and promising antigen for further evaluation in anti-HIV-1 vaccine strategies.
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Affiliation(s)
- Katia Mayol
- FRE2736 CNRS/bioMérieux, IFR128 BioSciences Lyon Gerland, 21 avenue Tony Garnier, 69365 Lyon cedex 07, France
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Shoji-Kawata S, Zhong Q, Kameoka M, Iwabu Y, Sapsutthipas S, Luftig RB, Ikuta K. The RING finger ubiquitin ligase RNF125/TRAC-1 down-modulates HIV-1 replication in primary human peripheral blood mononuclear cells. Virology 2007; 368:191-204. [PMID: 17643463 DOI: 10.1016/j.virol.2007.06.028] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2007] [Revised: 06/04/2007] [Accepted: 06/19/2007] [Indexed: 11/27/2022]
Abstract
CXCR4-using HIV-1 was previously shown to replicate more efficiently in a healthy donor-derived CD4(+) CD38(+) than in a CD4(+) CD38(-) T-cell subset after stimulation with interleukin (IL)-4. Here, we identified 3 cellular genes, which were expressed to a higher level in an IL-4-stimulated CD38(-) subset. One of the 3 genes, RNF125/TRAC-1, was involved in the down-regulation of HIV-1 replication not only in cell lines, but also in peripheral blood mononuclear cells. RNF125/TRAC-1 bears the RING finger domain, important for E3 ubiquitin protein ligase. Mutations in this domain of RNF125/TRAC-1 led to the loss of HIV-1 down-modulatory activity, suggesting that E3 ligase activity is necessary. In addition, the results of Northern blotting and reporter gene analysis indicated that RNF125/TRAC-1 function occurs at the viral transcription step. These results suggest that RNF125/TRAC-1 could function to recruit host factor(s) controlling HIV-1 transcription to the ubiquitin-proteasome pathway.
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Affiliation(s)
- Sanae Shoji-Kawata
- Department of Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
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Djoba Siawaya JF, Ruhwald M, Eugen-Olsen J, Walzl G. Correlates for disease progression and prognosis during concurrent HIV/TB infection. Int J Infect Dis 2007; 11:289-99. [PMID: 17446108 DOI: 10.1016/j.ijid.2007.02.001] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2006] [Revised: 11/09/2006] [Accepted: 02/01/2007] [Indexed: 12/11/2022] Open
Abstract
Mycobacterium tuberculosis (Mtb) and the human immunodeficiency virus (HIV) are both life-threatening pathogens in their own right, but their synergic effects on the immune system during co-infection markedly enhance their effect on the host. This review focuses on the bidirectional interaction between HIV and Mtb and discusses the relevance of sputum smear examination, CD4+ counts, viral load at baseline and after initiation of anti-retroviral therapy, as well as additional existing and new potential immune correlates of disease progression and prognosis. These markers include beta2-microglobulin, neopterin, tumor necrosis factor receptor II (TNFRII), CD8+/CD38+, soluble urokinase plasminogen activator receptor (suPAR) and CXCL10 (or IP-10).
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Affiliation(s)
- Joel Fleury Djoba Siawaya
- Immunology Unit, Department of Biomedical Sciences, DST/NRF Center of Excellence in Biomedical TB Research, Faculty of Health Sciences, University of Stellenbosch, PO Box 19063, Tygerberg 7505, South Africa.
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46
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Bahbouhi B, Landay A, Tenorio A, Al-Harthi L. HIV infection of primary CD4+ Th2 cells, defined by expression of the chemoattractant receptor-homologous (CRTH2), induces a Th0 phenotype. AIDS Res Hum Retroviruses 2007; 23:269-77. [PMID: 17331033 DOI: 10.1089/aid.2006.0151] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The association between HIV, cytokine profile, and disease progression is controversial. In this study, we evaluated whether HIV infection of a primary T helper-like type 2 cytokine (Th2) cell subset augments their cytokine profile. We utilized the CRTH2 (chemoattractant receptor-homologous) marker to identify CD4+ Th2 cells. Approximately 2-4% of CD4+ T cells are CRTH2+. CRTH2+ expression is confirmed to delineate a Th2 subset as indicated by robust inducible IL-4 response. CD4+ CRTH2+ T cells were also more inherently activated than their CRTH2-negative counterpart as indicated by a higher percent expression of CD69, CD45RO, CD95, CD25, and HLA-DR. CD4+CRTH2+ T cells were not terminally differentiated as indicated by expression of CD27 and CD28. In vitro HIV infection of primary human CD4 CRTH2T cells, independent of chemokine coreceptor usage, potently upregulated IFN-gamma production while still maintaining robust IL-4 expression. This Th0 (IFNgamma+ IL-4+) phenotype was upregulated in CD4+CRTH2+ T cells post-HIV infection by 18-fold, demonstrating a shift to a Th0 phenotype. Ex vivo studies also demonstrated that HIV+ patients exhibited a decline in CD4+CRTH2+ cells and a shift of this population toward cells that express both IFN-gamma and IL-4. Collectively, these data indicate that HIV replication in Th2 cells induces a Th0 phenotype. This phenomenon may be a deliberate viral escape mechanism to prevent the skewing of the immune response toward Th1 or Th2.
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Affiliation(s)
- Bouchaib Bahbouhi
- Department of Immunology/Microbiology , Rush University Medical Center, 1735 West Harrison Street, Chicago, IL 60612, USA
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Chabalgoity JA, Baz A, Rial A, Grille S. The relevance of cytokines for development of protective immunity and rational design of vaccines. Cytokine Growth Factor Rev 2007; 18:195-207. [PMID: 17347024 DOI: 10.1016/j.cytogfr.2007.01.016] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Cytokines are key regulators of the immune system that shape innate and adaptive immune responses. An adequate balance of the cytokine environment is critical to achieve protective immunity and to avoid immunopathology. Present knowledge allows a deeper understanding of the cytokine network and their sometimes conflicting roles in the development of immune responses, as well as their relevance in the establishment and maintenance of immunological memory. New insights have been gained into the role of different T cell subsets for protection against infection or tumor growth. The incorporation of cytokines as molecular adjuvants in vaccines has been attempted to strengthen vaccine-induced immune responses, and as a rational approach to modulate cytokine milieu in vivo and tailor host immunity for specific situations. These approaches have been tried in experimental models and veterinary species, and a few of them have entered into clinical trials. However, manipulating the cytokine network to modulate immune responses is not a simple task, because cytokine functions are complex and the final effects on the immune response will depend on timing and length of exposure, cell(s) targeted and other cytokines present in the same microenvironment. Here, we will review our present understanding on the role of cytokines in the development of effector and memory T cell responses. Also the potential use of cytokines as molecular adjuvant for vaccines against infectious diseases and cancer will be revised.
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Affiliation(s)
- Jose A Chabalgoity
- Laboratory for Vaccine Research, Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, Universidad de la Republica, Av. Navarro 3051, CP 11600, Uruguay.
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48
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Cheng X, Irimia D, Dixon M, Sekine K, Demirci U, Zamir L, Tompkins RG, Rodriguez W, Toner M. A microfluidic device for practical label-free CD4(+) T cell counting of HIV-infected subjects. LAB ON A CHIP 2007; 7:170-8. [PMID: 17268618 PMCID: PMC4028372 DOI: 10.1039/b612966h] [Citation(s) in RCA: 232] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2023]
Abstract
Practical HIV diagnostics are urgently needed in resource-limited settings. While HIV infection can be diagnosed using simple, rapid, lateral flow immunoassays, HIV disease staging and treatment monitoring require accurate counting of a particular white blood cell subset, the CD4(+) T lymphocyte. To address the limitations of current expensive, technically demanding and/or time-consuming approaches, we have developed a simple CD4 counting microfluidic device. This device uses cell affinity chromatography operated under differential shear flow to specifically isolate CD4(+) T lymphocytes with high efficiency directly from 10 microliters of unprocessed, unlabeled whole blood. CD4 counts are obtained under an optical microscope in a rapid, simple and label-free fashion. CD4 counts determined in our device matched measurements by conventional flow cytometry among HIV-positive subjects over a wide range of absolute CD4 counts (R(2) = 0.93). This CD4 counting microdevice can be used for simple, rapid and affordable CD4 counting in point-of-care and resource-limited settings.
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Affiliation(s)
- Xuanhong Cheng
- Surgical Services and Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospital for Children, Boston, Massachusetts, 02114, USA., Fax: 617-724-2999; Tel: 617-371-4876
| | - Daniel Irimia
- Surgical Services and Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospital for Children, Boston, Massachusetts, 02114, USA., Fax: 617-724-2999; Tel: 617-371-4876
| | - Meredith Dixon
- Parnters AIDS Research Center, Massachusetts General Hospital, Boston, Massachusetts, 02114, USA., Fax: 617-726-4691; Tel: 617-726-8099
| | - Kazuhiko Sekine
- Surgical Services and Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospital for Children, Boston, Massachusetts, 02114, USA., Fax: 617-724-2999; Tel: 617-371-4876
| | - Utkan Demirci
- Surgical Services and Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospital for Children, Boston, Massachusetts, 02114, USA., Fax: 617-724-2999; Tel: 617-371-4876
| | - Lee Zamir
- Parnters AIDS Research Center, Massachusetts General Hospital, Boston, Massachusetts, 02114, USA., Fax: 617-726-4691; Tel: 617-726-8099
| | - Ronald G. Tompkins
- Surgical Services and Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospital for Children, Boston, Massachusetts, 02114, USA., Fax: 617-724-2999; Tel: 617-371-4876
| | - William Rodriguez
- Parnters AIDS Research Center, Massachusetts General Hospital, Boston, Massachusetts, 02114, USA., Fax: 617-726-4691; Tel: 617-726-8099
- Division of AIDS, Harvard Medical School, and Brigham and Women’s Hospital, Boston, Massachusetts, 02114, USA
| | - Mehmet Toner
- Surgical Services and Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospital for Children, Boston, Massachusetts, 02114, USA., Fax: 617-724-2999; Tel: 617-371-4876
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Beaudoin G, Diker B, Angel JB, Copeland KFT. Effects of highly active antiretroviral therapy and immune recovery on CD8+ T-cell-mediated inhibition of HIV-1 transcription. J Acquir Immune Defic Syndr 2006; 43:393-400. [PMID: 16967042 DOI: 10.1097/01.qai.0000232916.35884.7b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
SUMMARY : To date, the relation between the CD8 antiviral factor (CAF) and clinical indicators of disease progression in HIV-1 infection (CD4 T-cell counts and viral load [VL]) is inconclusive. Particularly, the effect of antiretroviral therapy and immune recovery on CAF production remains unclear. Using a transient transfection assay and a reporter gene activated by the HIV-1 long terminal repeat (LTR), we analyzed CAF production in CD8 T cells of HIV-1-positive individuals divided into 3 groups: patients on protease inhibitor (PI)-based therapy, patients on nonnucleoside reverse transcriptase inhibitor (NNRTI)-based therapy, and patients receiving no therapy. We found that within the untreated group, CAF activity inversely correlated with VL and high CAF was associated with lower VLs over a period of 0.5 to 3 years. Furthermore, patients who were drug-naive demonstrated significantly higher CAF than untreated patients who had previously undergone antiretroviral therapy. CAF activity in treated patients was similar to CAF in drug-naive patients and higher than in off-treatment patients. There seemed to be a trend toward higher CAF in patients on NNRTI-based therapy compared with those on PI-based therapy. These results suggest that immune recovery after highly active antiretroviral therapy (HAART) contributes to the normalization of CAF levels in HIV-1-positive individuals. Furthermore, we have distinguished between CD8 T-cell-mediated suppression of HIV-1 replication and gene transcription.
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Affiliation(s)
- Greg Beaudoin
- Molecular Medicine Program, Ottawa Health Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada
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50
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Brown M, Mawa PA, Kaleebu P, Elliott AM. Helminths and HIV infection: epidemiological observations on immunological hypotheses. Parasite Immunol 2006; 28:613-23. [PMID: 17042933 PMCID: PMC1636684 DOI: 10.1111/j.1365-3024.2006.00904.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2006] [Accepted: 05/07/2006] [Indexed: 12/11/2022]
Abstract
Parasitic helminths have co-evolved with the mammalian immune system. Current hypotheses suggest that immunological stimulation in the presence of helminths is balanced by immuno-regulation and by the broad spectrum of mechanisms possessed by helminths for countering the host immune response. The degree to which this balance is perfected, and the mechanisms by which this is achieved, vary between helminth species; we suggest that this is reflected not only in the degree of pathology induced by helminths but also in a variety of relationships with HIV infection and HIV disease. Available epidemiological data regarding interactions between helminths and HIV are largely observational; results are variable and generally inconclusive. Well designed, controlled intervention studies are required to provide definitive information on the species-specific nature of these interactions and on the advantages, disadvantages and optimal timing of de-worming in relation to HIV infection.
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Affiliation(s)
- M Brown
- London School of Hygiene & Tropical Medicine, London, UK
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