A Low T Regulatory Cell Response May Contribute to Both Viral Control and Generalized Immune Activation in HIV Controllers

University of Toronto, Canada
PLoS ONE (Impact Factor: 3.23). 01/2011; 6(1):e15924. DOI: 10.1371/journal.pone.0015924
Source: PubMed


HIV-infected individuals maintaining undetectable viremia in the absence of therapy (HIV controllers) often maintain high HIV-specific T cell responses, which has spurred the development of vaccines eliciting HIV-specific T cell responses. However, controllers also often have abnormally high T cell activation levels, potentially contributing to T cell dysfunction, CD4+ T cell depletion, and non-AIDS morbidity. We hypothesized that a weak T regulatory cell (Treg) response might contribute to the control of viral replication in HIV controllers, but might also contribute to generalized immune activation, contributing to CD4+ T cell loss. To address these hypotheses, we measured frequencies of activated (CD38+ HLA-DR+), regulatory (CD4+CD25+CD127(dim)), HIV-specific, and CMV-specific T cells among HIV controllers and 3 control populations: HIV-infected individuals with treatment-mediated viral suppression (ART-suppressed), untreated HIV-infected "non-controllers" with high levels of viremia, and HIV-uninfected individuals. Despite abnormally high T cell activation levels, controllers had lower Treg frequencies than HIV-uninfected controls (P = 0.014). Supporting the propensity for an unusually low Treg response to viral infection in HIV controllers, we observed unusually high CMV-specific CD4+ T cell frequencies and a strong correlation between HIV-specific CD4+ T cell responses and generalized CD8+ T cell activation levels in HIV controllers (P ≤ 0.001). These data support a model in which low frequencies of Tregs in HIV controllers may contribute to an effective adaptive immune response, but may also contribute to generalized immune activation, potentially contributing to CD4 depletion.

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    • "Elevated markers of immune activation and bacterial translocation were found in EC as compared to HAART treated patients (Hunt et al., 2008, 2011), and these abnormalities were associated with lower CD4 + cell counts. Excess morbidity from non-AIDS conditions was also found in EC compared to HAART treated patients with undetectable viral load. "
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    ABSTRACT: HIV's ability to establish latent reservoirs of reactivation-competent virus is the major barrier to cure. "Shock and kill" methods consisting of latency-reversing agents (LRAs) followed by elimination of reactivating cells through cytopathic effects are under active development. However, the clinical efficacy of LRAs remains to be established. Moreover, recent studies indicate that reservoirs may not be reduced efficiently by either viral cytopathic or CD8(+) T-cell-mediated mechanisms. In this perspective, we highlight challenges to T-cell-mediated elimination of HIV reservoirs, including characteristics of responding T cells, aspects of the cellular reservoirs, and properties of the latent virus itself. We also discuss potential strategies to overcome these challenges by targeting the antiviral activity of T cells toward appropriate viral antigens following latency.
    Frontiers in Immunology 10/2015; 6. DOI:10.3389/fimmu.2015.00506
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    • "Elevated markers of immune activation and bacterial translocation were found in EC as compared to HAART treated patients (Hunt et al., 2008, 2011), and these abnormalities were associated with lower CD4+ cell counts. Excess morbidity from non-AIDS conditions was also found in EC compared to HAART treated patients with undetectable viral load. "
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    ABSTRACT: Accumulating data generated from persons who naturally control HIV without the need for antiretroviral treatment has led to significant insights into the possible mechanisms of durable control of AIDS virus infection. At the center of this control is the HIV-specific CD8 T cell response, and the basis for this CD8-mediated control is gradually being revealed. Genome wide association studies coupled with HLA sequence data implicate the nature of the HLA-viral peptide interaction as the major genetic factor modulating durable control of HIV, but host genetic factors account for only around 20% of the variability in control. Other factors including specific functional characteristics of the TCR clonotypes generated in vivo, targeting of vulnerable regions of the virus that lead to fitness impairing mutations, immune exhaustion, and host restriction factors that limit HIV replication all have been shown to additionally contribute to control. Moreover, emerging data indicate that the CD8(+) T cell response may be critical for attempts to purge virus infected cells following activation of the latent reservoir, and thus lessons learned from elite controllers (ECs) are likely to impact the eradication agenda. On-going efforts are also needed to understand and address the role of immune activation in disease progression, as it becomes increasingly clear that durable immune control in ECs comes at a cost. Taken together, the research achievements in the attempt to unlock the mechanisms behind natural control of HIV will continue to be an important source of insights and ideas in the continuous search after an effective HIV vaccine, and for the attempts to achieve a sterilizing or functional cure in HIV positive patients with progressive infection.
    Frontiers in Immunology 06/2013; 4:162. DOI:10.3389/fimmu.2013.00162
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    • "This is illustrated by the modest success of the Thai vaccine trial, in which decreased HIV acquisition was observed with a CD4 + T cell-inducing vaccine [17]. Studying subpopulations of untreated HIV-infected patients with slow disease progression, as defined by immunologic or virologic parameters, allows us to obtain more insights into the protective mechanisms [18] [19]. Long-term non-progressors (LTNP) remain asymptomatic for many years and maintain high CD4 cell counts without antiretroviral therapy (ART), whereas viral controllers (VC) spontaneously suppress viral replication [19]. "
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    ABSTRACT: A recombinant fusion protein (F4) consisting of HIV-1 p17, p24, reverse transcriptase (RT) and Nef, adjuvanted with AS01, induced strong and broad CD4(+) T-cell responses in healthy volunteers. Here we compare these vaccine-induced CD4(+) T-cell responses with the ones induced by natural infection in patients with varying disease courses. Thirty-eight HIV-infected, antiretroviral treatment-naïve subjects were classified into four categories: 8 long-term non-progressors (infection ≥7 years; CD4(+) T-cells ≥500/μL), 10 recently infected individuals (infection ≤2 years; CD4(+) T-cells ≥500/μL), 10 typical early progressors (CD4(+) T-cells ≤350/μL), and 10 viral controllers (plasma HIV-1 RNA <1000copies/mL). Peripheral blood mononuclear cells were stimulated in vitro with p17, p24, RT and Nef peptide pools and analyzed by flow cytometry for expression of IL-2, IFN-γ, TNF-α and CD40L. CD4(+) T-cell responses were compared to those measured with the same method in 50 HIV-uninfected subjects immunized with the F4/AS01 candidate vaccine (NCT00434512). After in vitro stimulation with p17, p24 and RT antigen viral controllers had significantly more CD4(+) T-cells co-expressing IL-2, IFN-γ and TNF-α than other HIV patient categories. The magnitude and quality of these responses in viral controllers were comparable to those observed in F4/AS01 vaccine recipients. In contrast with viral controllers, triple cytokine producing CD4(+) T-cells in vaccinees also expressed CD40L. Subjects who spontaneously control an HIV infection display polyfunctional CD4(+) T cell responses to p17, p24, RT and Nef, with similar magnitude and qualities as those induced in healthy volunteers by an adjuvanted HIV candidate vaccine (F4/AS01).
    Vaccine 05/2013; 31(36). DOI:10.1016/j.vaccine.2013.05.021 · 3.62 Impact Factor
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