Abstract Body

The development of single-pill anti-retroviral therapies (ART) with tolerable toxicity profiles have proven highly effective in suppressing HIV viremia to clinically undetectable levels in people living with HIV (PLWH). However, ART alone is incapable of purging the pool of long-lived, tissue-resident, quiescent CD4+ T-cells harboring latent, replication-competent viral genomes. These ‘viral reservoirs’, maintained despite ART, comprise cells enriched for the expression of co-inhibitory receptors (Co-IR), which enforce state of T cell exhaustion. In this presentation, I will discuss advances in using strategies targeting T cell exhaustion and homeostasis to induce viral reactivation during ART and viral control in absence of ART in SIV-infected rhesus macaques (RMs). In addition to PD-1+ T follicular helper cells (TFH), lymph node CTLA-4+ CD4+ T cells harbor robust levels of replication competent SIV-DNA. To stimulate the activation of Co-IR-expressing T cells, we have performed combination blockades of PD-1 and CTLA-4 during ART, which synergized to induce T cell proliferation and resulted in clonally diverse plasma viral reactivation. As the blockade failed to enhance the activity of SIV-specific T-cell responses, these data suggest that the reversal of T-cell exhaustion alone, in the absence of viral antigen, is insufficient to stimulate a reduction of viral content in tissue. Furthermore, concurrent studies utilizing CD8 depleting mAbs described a role for CD8+ T cells in regulating viral latency via non-cytolytic mechanisms. Notably, our most recent data shows that interleukin(IL)-10 signaling, which regulates T cell survival, differentiation and Co-IR expression, promotes viral persistence. Consistently, in an ongoing nonhuman primate study simultaneous IL-10 neutralization and PD-1 blockade performed following ART analytical therapy interruption synergized to induce viral control. In summary, our data demonstrates that strategies targeting the maintenance of the cells known to harbor the viral reservoir in combination with improving antiviral responses might represent a novel approach to control viremia in the absence of ART. Understanding how these complex processes promote viral persistence and how they might be further targeted by emerging therapeutics represent both a formidable challenge and an exciting opportunity for the years to come.