CD8 + T-cell responses in HIV controllers: potential implications for novel HIV remission strategies

Abstract

Purpose of review: Immunological studies of spontaneous HIV and simian virus (SIV) controllers have identified virus-specific CD8 + T cells as a key immune mechanism of viral control. The purpose of this review is to consider how knowledge about the mechanisms that are associated with CD8 + T cell control of HIV/SIV in natural infection can be harnessed in HIV remission strategies.

Recent findings: We discuss characteristics of CD8 + T-cell responses that may be critical for suppressing HIV replication in spontaneous controllers comprising HIV antigen recognition including specific human leukocyte antigen types, broadly cross-reactive T cell receptors and epitope targeting, enhanced expansion and antiviral functions, and localization of virus-specific T cells near sites of reservoir persistence. We also discuss the need to better understand the timing of CD8 + T-cell responses associated with viral control of HIV/SIV during acute infection and after treatment interruption as well as the mechanisms by which HIV/SIV-specific CD8 + T cells coordinate with other immune responses to achieve control.

Summary: We propose implications as to how this knowledge from natural infection can be applied in the design and evaluation of CD8 + T-cell-based remission strategies and offer questions to consider as these strategies target distinct CD8 + T-cell-dependent mechanisms of viral control.

FIGURE 1

Key CD8⁺ T-cell features to target for HIV remission. HIV-specific CD8⁺ T cells from elite controllers are more likely to be restricted by specific HLA types, target epitopes derived from the relatively evolutionarily conserved/constrained regions of the HIV genome, and to have broadly-reactive T cell receptors (TCRs) capable of recognizing variant epitopes. Evaluated directly ex vivo, they occupy a T cell memory-like differentiation state with high TCF-1 expression and low levels of expression of coinhibitory receptors such as PD-1 and they are more likely to accumulate in B cell follicles in lymphoid tissue (due to expression of CXCR5). After stimulation with HIV antigens in vitro, they demonstrate enhanced expansion capacity and an ability to generate secondary effector cells that have enhanced antiviral function.

Box 1

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FIGURE 2

CD8⁺ T-cell characteristics of viral control: Potential implications for HIV remission strategies. (a) List of implication for novel HIV remission strategies and remaining questions to be answered. (b) HIV controllers grouped and analyzed for the different CD8⁺ T-cell characteristics associated with viral control will inform HIV remission strategies and need to be targeted in combination with other factors contributing to viral control.