Research ArticleHIV

Elite control of HIV is associated with distinct functional and transcriptional signatures in lymphoid tissue CD8+ T cells

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Science Translational Medicine  18 Dec 2019:
Vol. 11, Issue 523, eaax4077
DOI: 10.1126/scitranslmed.aax4077

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The secret lives of CD8+s

CD8+ T cells are often referred to as cytotoxic lymphocytes, but their functions extend beyond lysis of targets. Moreover, resident CD8+ T cells are not identical to their better studied circulating counterparts. To better understand functions of highly effective lymphoid CD8+ T cells, Nguyen et al. sampled lymph nodes from HIV elite controllers. Compared with cells from people with progressive disease, the elite controller cells had a distinct transcriptional profile and were able to suppress viral replication in the absence of cytolysis. CD8+ T cells from elite controllers translated proteins more efficiently, which could contribute to viral control. These results elucidate natural mechanisms of HIV control that could be informative for cure efforts or vaccine design.

Abstract

The functional properties of circulating CD8+ T cells have been associated with immune control of HIV. However, viral replication occurs predominantly in secondary lymphoid tissues, such as lymph nodes (LNs). We used an integrated single-cell approach to characterize effective HIV-specific CD8+ T cell responses in the LNs of elite controllers (ECs), defined as individuals who suppress viral replication in the absence of antiretroviral therapy (ART). Higher frequencies of total memory and follicle-homing HIV-specific CD8+ T cells were detected in the LNs of ECs compared with the LNs of chronic progressors (CPs) who were not receiving ART. Moreover, HIV-specific CD8+ T cells potently suppressed viral replication without demonstrable cytolytic activity in the LNs of ECs, which harbored substantially lower amounts of CD4+ T cell–associated HIV DNA and RNA compared with the LNs of CPs. Single-cell RNA sequencing analyses further revealed a distinct transcriptional signature among HIV-specific CD8+ T cells from the LNs of ECs, typified by the down-regulation of inhibitory receptors and cytolytic molecules and the up-regulation of multiple cytokines, predicted secreted factors, and components of the protein translation machinery. Collectively, these results provide a mechanistic framework to expedite the identification of novel antiviral factors, highlighting a potential role for the localized deployment of noncytolytic functions as a determinant of immune efficacy against HIV.

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