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

Abstract

Purpose of reviewImmunological 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 findingsWe 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.SummaryWe 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.

CD8+ cells and small viral reservoirs facilitate post-ART control of SIV in Mauritian cynomolgus macaques

“…A relevant animal model would enable the immunological and virological correlates of PTC to be characterized. Consistent PTC in MCMs without known protective MHC alleles in this study aligns with the observation that HIV+ PTCs are not enriched for protective MHC alleles 2,8,9,30 . PTC in MCMs could thus be a good model for PTC in humans.…”

“…These individuals are termed post-treatment controllers (PTCs) 1-4 . While specific major histocompatibility complex (MHC) alleles are associated with spontaneous control of HIV without ART (elite control; EC), MHC alleles are not thought to influence the likelihood of becoming a PTC 2,[5][6][7][8][9] . The underlying mechanisms that lead to PTC are poorly understood.…”

Generating and measuring effective vaccine-elicited HIV-specific CD8+ T cell responses

“…Although most individuals with HIV generate HIVspecific CD8 þ T cell responses early in infection [3,5,6,16,17], the majority of people with HIV cannot control viremia without antiretroviral therapy (ART). Rare individuals known as elite controllers [<1% of people with HIV (PWH)] do control viremia to undetectable levels in the absence of ART, and several lines of evidence suggest a role for CD8 þ T cells in establishing and maintaining this control [3,4,18 && , [19][20][21]. Direct control of infection by CD8 þ T cells has been demonstrated by experiments in simian immunodeficiency virus (SIV)-or simian-human immunodeficiency virus (SHIV)-infected nonhuman primates (NHPs) in which CD8a or CD8b depletion led to an increase in viral load [22][23][24][25][26][27].…”

Challenges of HIV therapeutic vaccines clinical trials design

“…Therapeutic vaccines could have an important role on functional cure and are being tested alone or in combination trials with immunomodulatory agents, broadly neutralizing antibodies (bNAbs) and/or latency reversing in the so-called “kick and kill” strategies [6,7]. The purpose of therapeutic vaccines is to modify host's immune response to HIV, either by redirecting it to the most conserved/vulnerable regions of the HIV viral proteome to mimic the response of spontaneous controllers [8 ▪ ,9] or by increasing its depth to cover more viral diversity [10].…”