Th17 cells and regulatory T cells in elite control over HIV and SIV.
ABSTRACT 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.
Article: Tuberculosis and HIV Coinfection[Show abstract] [Hide abstract]
ABSTRACT: Tuberculosis (TB) and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) constitute the main burden of infectious disease in resource-limited countries. In the individual host, the two pathogens, Mycobacterium tuberculosis and HIV, potentiate one another, accelerating the deterioration of immunological functions. In high-burden settings, HIV coinfection is the most important risk factor for developing active TB, which increases the susceptibility to primary infection or reinfection and also the risk of TB reactivation for patients with latent TB. M. tuberculosis infection also has a negative impact on the immune response to HIV, accelerating the progression from HIV infection to AIDS. The clinical management of HIV-associated TB includes the integration of effective anti-TB treatment, use of concurrent antiretroviral therapy (ART), prevention of HIV-related comorbidities, management of drug cytotoxicity, and prevention/treatment of immune reconstitution inflammatory syndrome (IRIS). Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.Cold Spring Harbor Perspectives in Medicine 02/2015; DOI:10.1101/cshperspect.a017871 · 7.56 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Mucosal Th17 cells play an important role in maintaining gut epithelium integrity and thus prevent microbial translocation. Chronic HIV infection is characterized by mucosal Th17 cell depletion, microbial translocation and subsequent immune-activation, which remain elevated despite antiretroviral therapy (ART) correlating with increased mortality. However, when Th17 depletion occurs following HIV infection is unknown. We analyzed mucosal Th17 cells in 42 acute HIV infection (AHI) subjects (Fiebig (F) stage I-V) with a median duration of infection of 16 days and the short-term impact of early initiation of ART. Th17 cells were defined as IL-17+ CD4+ T cells and their function was assessed by the co-expression of IL-22, IL-2 and IFNc. While intact during FI/II, depletion of mucosal Th17 cell numbers and function was observed during FIII correlating with local and systemic markers of immune-activation. ART initiated at FI/II prevented loss of Th17 cell numbers and function, while initiation at FIII restored Th17 cell numbers but not their polyfunctionality. Furthermore, early initiation of ART in FI/II fully reversed the initially observed mucosal and systemic immune-activation. In contrast, patients treated later during AHI maintained elevated mucosal and systemic CD8+ T-cell activation post initiation of ART. These data support a loss of Th17 cells at early stages of acute HIV infection, and highlight that studies of ART initiation during early AHI should be further explored to assess the underlying mechanism of mucosal Th17 function preservation.PLoS Pathogens 12/2014; 8(9). DOI:10.1371/journal.ppat.1004543 · 8.14 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Introduction: During HIV infection the severe depletion of intestinal CD4(+) T-cells is associated with microbial translocation, systemic immune activation, and disease progression. This study examined intestinal and peripheral CD4(+) T-cell subsets reconstitution under combined antiretroviral therapy (cART), and systemic immune activation markers. Methods: This longitudinal single-arm pilot study evaluates CD4(+) T cells, including Th1 and Th17, in gut and blood and soluble markers for inflammation in HIV-infected individuals before (M0) and after eight (M8) months of cART. From January 2010 to December 2011, 10 HIV-1 naive patients were screened and 9 enrolled. Blood and gut CD4(+) T-cells subsets and cellular immune activation were determined by flow-cytometry and plasma soluble CD14 by ELISA. CD4(+) Th17 cells were detected in gut biopsies by immunohistochemistry. Microbial translocation was measured by limulus-amebocyte-lysate assay to detect bacterial lipopolysaccharide (LPS) and PCR Real Time to detect plasma bacterial 16S rDNA. Results: Eight months of cART increased intestinal CD4(+) and Th17 cells and reduced levels of T-cell activation and proliferation. The magnitude of intestinal CD4(+) T-cell reconstitution correlated with the reduction of plasma LPS. Importantly, the magnitude of Th17 cells reconstitution correlated directly with blood CD4(+) T-cell recovery. Conclusion: Short-term antiretroviral therapy resulted in a significant increase in the levels of total and Th17 CD4(+) T-cells in the gut mucosa and in decline of T-cell activation. The observation that pre-treatment levels of CD4(+) and of CD8(+) T-cell activation are predictors of the magnitude of Th17 cell reconstitution following cART provides further rationale for an early initiation of cART in HIV-infected individuals.PLoS ONE 10/2014; 9(10):e109791. DOI:10.1371/journal.pone.0109791 · 3.53 Impact Factor