Research ArticleHIV

Delayed differentiation of potent effector CD8+ T cells reducing viremia and reservoir seeding in acute HIV infection

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Science Translational Medicine  15 Feb 2017:
Vol. 9, Issue 377, eaag1809
DOI: 10.1126/scitranslmed.aag1809

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Peak HIV viremia pushes CD8+ T cells

Aside from CD4+ T cell death, the immune system in chronically infected HIV patients is dysfunctional, including the inability of CD8+ T cells to control the virus. Animal studies with simian immunodeficiency virus have suggested that early CD8+ T cell responses may be capable of reducing viral burden, but getting access to patient samples at the earliest stage of infection is challenging. Takata et al. examined a large cohort of acutely infected patients that were given antiretroviral therapy (ART) upon enrollment in the study to evaluate T cell activation and HIV viral load over time, allowing them to parse out immune function (or dysfunction) based on acute stages of infection. They saw that CD8+ T cell responses were a little slow to ramp up but that activated CD8+ T cells present after initiation of ART could reduce the magnitude of the viral reservoir. These findings confirm that targeting CD8+ T cells at the early stage of infection could lead to viral eradication.

Abstract

CD8+ T cells play a critical role in controlling HIV viremia and could be important in reducing HIV-infected cells in approaches to eradicate HIV. The simian immunodeficiency virus model provided the proof of concept for a CD8+ T cell–mediated reservoir clearance but showed conflicting evidence on the role of these cells to eliminate HIV-infected cells. In humans, HIV-specific CD8+ T cell responses have not been associated with a reduction of the HIV-infected cell pool in vivo. We studied HIV-specific CD8+ T cells in the RV254 cohort of individuals initiating ART in the earliest stages of acute HIV infection (AHI). We showed that the HIV-specific CD8+ T cells generated as early as AHI stages 1 and 2 before peak viremia are delayed in expanding and acquiring effector functions but are endowed with higher memory potential. In contrast, the fully differentiated HIV-specific CD8+ T cells at peak viremia in AHI stage 3 were more prone to apoptosis but were associated with a steeper viral load decrease after ART initiation. Their capacity to persist in vivo after ART initiation correlated with a lower HIV DNA reservoir. These findings demonstrate that HIV-specific CD8+ T cell magnitude and differentiation are delayed in the earliest stages of infection. These results also demonstrate that potent HIV-specific CD8+ T cells contribute to the reduction of the pool of HIV-producing cells and the HIV reservoir seeding in vivo and provide the rationale to design interventions aiming at inducing these potent responses to cure HIV infection.

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