CD8+ cells and small viral reservoirs facilitate post-ART control of SIV replication in M3+ Mauritian cynomolgus macaques initiated on ART two weeks post-infection

Abstract

Sustainable HIV remission after antiretroviral therapy (ART) withdrawal, or post-treatment control (PTC), remains a top priority for HIV treatment. We observed surprising PTC in an MHC-haplomatched cohort of MHC-M3+ SIVmac239+ Mauritian cynomolgus macaques (MCMs) initiated on ART at two weeks post-infection (wpi). None of the MCMs possessed MHC haplotypes previously associated with SIV control. For six months after ART withdrawal, we observed undetectable or transient viremia in seven of the eight MCMs, despite detecting replication competent SIV using quantitative viral outgrowth assays. In vivo depletion of CD8α+ cells induced rebound in all animals, indicating the observed PTC was mediated, at least in part, by CD8α+ cells. With intact proviral DNA assays, we found that MCMs had significantly smaller viral reservoirs two wpi than a cohort of identically infected rhesus macaques, a population that rarely develops PTC. We found a similarly small viral reservoir among six additional SIV+ MCMs in which ART was initiated at eight wpi, some of whom exhibited viral rebound. These results suggest that an unusually small viral reservoir is a hallmark among SIV+ MCMs. By evaluating immunological differences between MCMs that did and did not rebound, we identified that PTC was associated with a reduced frequency of CD4+ and CD8+ lymphocyte subsets expressing exhaustion markers. Together, these results suggest a combination of small reservoirs and immune-mediated virus suppression contribute to PTC in MCMs. Further, defining the immunologic mechanisms that engender PTC in this model may identify therapeutic targets for inducing durable HIV remission in humans.

Predictors of HIV rebound differ by timing of antiretroviral therapy initiation

“…In contrast, HIV-specific antibody levels largely reflected the size and activity of the HIV reservoir, likely because the reservoir continues to stimulate the humoral responses ( 9 ). In human and nonhuman primate studies, the role of T cell exhaustion in predicting the timing of HIV rebound ( 25 , 26 ), and our results showing that higher frequency of effector T cells and HIV-specific CD8 + CD107a + cells is associated with delayed rebound, together highlight cellular immunity as another key mediator of HIV rebound timing that deserves additional investigation ( 27 – 29 ). Furthermore, our results provide some of the first evidence that higher levels of LBP, sCD14, and sCD163 are associated with more rapid viral rebound, highlighting the potential influence of microbial translocation and microbiome-associated myeloid activation with the timing of HIV rebound.…”

Understanding early HIV-1 rebound dynamics following antiretroviral therapy interruption: The importance of effector cell expansion

“…Individuals, who experience rapid viral rebound, are generally referred to as non-controllers (NC), while those who control are termed post-treatment controllers (PTC). The generation of post-treatment control appears to be affected by external factors such as the timing of ART initiation [17,22,[25][26][27][28], and in human and nonhuman primate models by viral suppression mediated by CD8+ cells [29][30][31][32][33][34].…”