Curr Opin HIV AIDS.
Hartigan-O'Connor DJ , Hirao LA , McCune JM , Dandekar S .
Division of Experimental Medicine, Department of Medicine, University of California, San
Francisco, USA. email@example.com
PURPOSE OF REVIEW:
We present current findings about two subsets of CD4+ T cells that play an important part in the initial host response to infection with the HIV type 1: those producing IL-17 (Th17 cells) and those with immunosuppressive function (CD25+FoxP3+ regulatory T cells or T-reg). The role of these cells in the control of viral infection and immune activation as well as in the prevention of immune deficiency in HIV-infected elite controllers will be examined. We will also discuss the use of the simian immunodeficiency virus (SIV)-infected macaque model of
AIDS to study the interplay between these cells and lentiviral infection in vivo.
Study of Th17 cells in humans and nonhuman primates (NHPs) has shown that depletion of these cells is associated with the dissemination of microbial products from the infected gut, increased systemic immune activation, and disease progression. Most impressively, having a smaller Th17-cell compartment has been found to predict these outcomes. T-reg have been associated with the reduced antiviral T-cell responses but not with the suppression of generalized T cell activation. Both cell subsets influence innate immune responses and, in doing so, may shape the inflammatory milieu of the host at infection.
Interactions between Th17 cells, T-reg, and cells of the innate immune system influence the course of HIV and SIV infection from its earliest stages, even before the appearance of adaptive immunity. Such interactions may be pivotal for elite control over disease progression.
2010 Feb 20;24(4):491-502.
Prendergast A , Prado JG , Kang YH , Chen F , Riddell LA , Luzzi G , Goulder P , Klenerman P .
Department of Paediatrics, University of Oxford, South Parks Road, Oxford, UK. firstname.lastname@example.org
CD4 T-cell depletion is central to HIV pathogenesis. However, the relative impact of HIV on
Th17 and regulatory T cell (Treg) subsets remains unclear. CD161 CD4 cells are a recently identified, gut-homing Th17 precursor population. The balance between pro-inflammatory
Th17 and immunoregulatory Tregs may be critical in HIV pathogenesis. This study addressed changes in CD161, Th17 and Treg subsets during untreated HIV infection.
Peripheral blood mononuclear cells were isolated from HIV-infected and HIV-uninfected individuals and stained to characterize CD161 CD4 cells, Th17 cells [by elaboration of interleukin (IL)-17A], Tregs (CD3CD4CD25FoxP3 cells) and CD8 activation (CD38/HLA-
DR cells). In-vitro infectability of CD161 and Th17 cells by HIV was assessed in healthy donor CD4 cells by intracellular p24 expression.
Peripheral blood Th17 cells were depleted 10-fold in HIV-infected, compared to HIVuninfected individuals (P < 0.0001) across a range of disease stages, accompanied by a significant reduction of CD161 T cells (P = 0.024). Both Th17 cells and CD161 CD4 T cells were permissive to HIV replication in vitro. Profound loss of Th17 cells before the onset of advanced disease contrasted with a gradual decline in absolute Tregs during HIV disease progression in untreated individuals followed longitudinally (R = 0.71, P = 0.003). Loss of
Tregs was associated with increased immune activation (R = -0.33, P = 0.03).
HIV-infected individuals showed profound loss of Th17 cells, which may impair mucosal immunity, and reduced CD161 CD4 cells, which may limit Th17 reconstitution. A gradual decline in Tregs during disease progression was associated with increased immune activation.
Curr Opin HIV AIDS.
Dandekar S , George MD ,
Department of Medical Microbiology and Immunology, University of California-Davis, CA,
PURPOSE OF REVIEW:
We will present recent studies on a subset of CD4 T helper cells, Th17 cells, that appears to be critical for regulating gut mucosal immune responses against extracellular microbial pathogens and may serve as a link between innate and adaptive immune responses.
Implications of the loss of Th17 CD4 T cells in HIV infection will be discussed in relation to the chronic immune activation and HIV pathogenesis.
Severe depletion of CD4 T cells occurs in the gut mucosa during primary HIV and simian immunodeficiency virus infections. A pronounced loss of mucosal Th17 CD4 T cells in the simian immunodeficiency virus-infected rhesus macaque model of AIDS is linked to impaired immune responses in the gut mucosa to an enteric pathogen, Salmonella typhimurium, leading to the lack of local control of the pathogen and its translocation. Recovery of the gut mucosal immune system during highly active antiretroviral therapy is slow and incomplete compared with the peripheral blood compartment. Recent studies suggest that the replenishment of Th17
CD4 T cells in the gut mucosa during highly active antiretroviral therapy, or during nonpathogenic simian immunodeficiency virus infections in the nonhuman primate models, correlates with better restoration and function of the gut mucosal immune system.
A better understanding of the role of Th17 CD4 cells in the generation of mucosal immune responses to enteric pathogens and maintenance of the intestinal epithelial integrity in HIVinfected patients will help in the development of novel strategies to modulate and enhance mucosal immune system and its function.
Curr Opin HIV AIDS.
Kanwar B , Favre D , McCune JM .
Division of Experimental Medicine, Department of Medicine, University of California-San
Francisco, CA 94110, USA.
PURPOSE OF REVIEW:
The present review discusses recent reports showing that reciprocal changes in T helper interleukin-17-secreting CD4 Th17 cells and CD4CD25FoxP3 regulatory T cells (Tregs) may play a role in the progressive disease caused by the HIV and by simian immunodeficiency virus.
Studies in nonhuman primate models of lentiviral infection and in HIV-infected human individuals have shown that pathogenic infection is associated with loss of Th17 cells and an increase in the frequency of Tregs. Because interleukin-17 serves to maintain the integrity of the mucosal barrier, loss of Th17 cells may permit the increase in microbial translocation across the gastrointestinal mucosa that is observed in pathogenic lentiviral disease. It remains unclear, however, whether Th17 cells are preferentially infected or if, instead, their loss is induced by bystander effects of lentiviral infection, for example, the induction of indoleamine
Progressive lentiviral disease is associated with preferential depletion of Th17 cells and loss of Th17/Treg balance. Further analysis of such changes in the composition of subset CD4 T helper and Tregs may shed new light on the immunopathology of HIV disease and suggest new strategies for therapeutic and preventive interventions.
[PubMed - indexed for MEDLINE]
Curr Opin HIV AIDS.
Elhed A , Unutmaz D .
Department of Microbiology, New York University School of Medicine, New York, NY
PURPOSE OF REVIEW:
This review summarizes the recent literature about the potential perturbation and role of Th17 cells in HIV pathogenesis. We discuss the recent findings on Th17 deficiency in HIV/simian immunodeficiency virus (SIV) infection and how this deficiency may impact the mucosal host defenses, potentially contributing to chronic immune activation.
Th17 cells have been implicated in host defense against a variety of pathogens and are involved in the pathogenesis of autoimmune diseases. Recently, Th17 cells were shown to be perturbed during HIV infection in humans and SIV infection in nonhuman primates. Th17 cells were found to be infected in vitro by HIV and SIV and are significantly depleted in the gastrointestinal tract of HIV-infected individuals. In monkeys, Th17 cells are only depleted in the pathogenic SIV infection of rhesus macaques, which correlates with the progression to
AIDS in these primates, whereas they remain intact in the nonpathogenic SIV infection of
African green monkeys or sooty mangabeys.
Th17 cells appear to be perturbed during HIV and SIV infection. This finding could have important implications in understanding the disruption of mucosal defenses in the gastrointestinal tract and potentially in predicting opportunistic infections during the course of
2008 May 11;22(8):990-2.
Ndhlovu LC , Chapman JM , Jha AR , Snyder-Cappione JE ,
, Leal FE , Boland BS ,
Norris PJ , Rosenberg MG , Nixon DF .
Division of Experimental Medicine, San Francisco General Hospital, Department of
Medicine, University of California, San Francisco, California 94110, USA. email@example.com
IL-17 is proinflammatory cytokine secreted by a unique CD4+ T (Th17) cell subset and proposed to play a role in host defense. We hypothesized that Th17 cells are lost in HIV-1 infection. HIV-1-infected children with plasma viremia below 50 copies/ml had IL-17 production, whereas those with detectable viremia had minimal secretion. These results imply viral-mediated destruction or impairment of Th17 cells and argue for complete suppression of viremia for reconstitution of Th17 cells.
2008 Nov;1(6):475-88. Epub 2008 Sep 10.
Macal M , Sankaran S , Chun TW , Reay E , Flamm J , Prindiville TJ , Dandekar S .
Department of Medical Microbiology and Immunology, University of California, Davis,
Human immunodeficiency virus (HIV) infection leads to severe CD4+ T-cell depletion in gutassociated lymphoid tissue (GALT) that persists despite the initiation of highly active antiretroviral therapy (HAART). It is not known whether restoration of gut mucosal CD4+ T cells and their functions is feasible during therapy and how that relates to immune correlates and viral reservoirs. Intestinal biopsies and peripheral blood samples from HIV-infected patients who were either HAART naive or on long-term HAART were evaluated. Our data demonstrated that gut CD4+ T-cell restoration ranged from modest (<50%) to high (>50%), compared with uninfected controls. Despite persistent CD4+ T-cell proviral burden and residual immune activation in GALT during HAART, effective CD4+ T-cell restoration
(>50%) was achieved, which was associated with enhanced Th17 CD4+ T-cell accumulation and polyfunctional anti-HIV cellular responses. Our findings suggest that a threshold of>50%
CD4+ T-cell restoration may be sufficient for polyfunctional HIV-specific T cells with implications in the evaluation of vaccines and therapeutics.
2009 Aug;15(8):893-900. Epub 2009 Jun 21.
Chomont N , El-Far M , Ancuta P , Trautmann L , Procopio FA , Yassine-Diab B , Boucher G ,
Boulassel MR , Ghattas G , Brenchley JM , Schacker TW , Hill BJ , Douek DC , Routy JP ,
Haddad EK ,
Laboratoire d'Immunologie, Centre de Recherche du Centre Hospitalier de l'Université de
Montréal Saint-Luc, Montréal, Québec, Canada.
HIV persists in a reservoir of latently infected CD4(+) T cells in individuals treated with highly active antiretroviral therapy (HAART). Here we identify central memory (T(CM)) and transitional memory (T(TM)) CD4(+) T cells as the major cellular reservoirs for HIV and find that viral persistence is ensured by two different mechanisms. HIV primarily persists in
T(CM) cells in subjects showing reconstitution of the CD4(+) compartment upon HAART.
This reservoir is maintained through T cell survival and low-level antigen-driven proliferation and is slowly depleted with time. In contrast, proviral DNA is preferentially detected in
T(TM) cells from aviremic individuals with low CD4(+) counts and higher amounts of interleukin-7-mediated homeostatic proliferation, a mechanism that ensures the persistence of these cells. Our results suggest that viral eradication might be achieved through the combined use of strategic interventions targeting viral replication and, as in cancer, drugs that interfere with the self renewal and persistence of proliferating memory T cells.
2009 Oct;5(10):e1000646. Epub 2009 Oct 30.
Casazza JP , Brenchley JM , Hill BJ , Ayana R , Ambrozak D , Roederer M , Douek DC , Betts
MR , Koup RA .
Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, USA. firstname.lastname@example.org
Induction of a functional subset of HIV-specific CD4+ T cells that is resistant to HIV infection could enhance immune protection and decrease the rate of HIV disease progression.
CMV-specific CD4+ T cells, which are less frequently infected than HIV-specific CD4+ T cells, are a model for such an effect. To determine the mechanism of this protection, we compared the functional response of HIV gag-specific and CMV pp65-specific CD4+ T cells in individuals co-infected with CMV and HIV. We found that CMV-specific CD4+ T cells rapidly up-regulated production of MIP-1alpha and MIP-1beta mRNA, resulting in a rapid increase in production of MIP-1alpha and MIP-1beta after cognate antigen stimulation.
Production of beta-chemokines was associated with maturational phenotype and was rarely seen in HIV-specific CD4+ T cells. To test whether production of beta-chemokines by CD4+
T cells lowers their susceptibility to HIV infection, we measured cell-associated Gag DNA to assess the in vivo infection history of CMV-specific CD4+ T cells. We found that CMVspecific CD4+ T cells which produced MIP-1beta contained 10 times less Gag DNA than did those which failed to produce MIP-1beta. These data suggest that CD4+ T cells which produce MIP-1alpha and MIP-1beta bind these chemokines in an autocrine fashion which decreases the risk of in vivo HIV infection.