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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    • "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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