CD8ɑ+ cells suppress SIV replication without evidence of viral immune escape during post treatment control

Post-treatment control (PTC) is a rare phenomenon in which people living with HIV (PLWH) maintain viral control following ART interruption. Characterizing virus populations present in PTCs may help elucidate mechanisms of immunologic control, but this is challenging without detectable plasma viremia. To model PTC, eight Mauritian cynomolgus macaques (MCM) were infected with barcoded SIVmac239M and began an 8-month ART regimen two weeks post-infection (wpi). Six months following ART interruption, all MCM were rechallenged with non-barcoded SIVmac239 followed by CD8ɑ+ cell depletion two months later. Animals were grouped as viremic (n=5) or aviremic (n=3) based on the detection of plasma viremia between ART interruption and CD8ɑ+ cell depletion; all animals became viremic post-depletion. Barcode sequencing of plasma virus revealed that lineages with high pre-ART viral loads dominated the rebounding populations post-depletion and detectable rechallenge virus in two animals post-depletion. Additional sequencing of three CD8+ T cell epitopes within plasma viruses identified point mutations only in viruses isolated from the viremic group post-depletion. A second cohort of 5 MCM who initiated ART 8 wpi was examined to identify the impact of the timing of ART initiation on viral epitope diversity and showed increased diversity prior to ART initiation and following ART interruption. These results suggest that early ART initiation is associated with reduced diversity within cytotoxic T lymphocyte (CTL) epitopes and a longer time to rebound, as well as highlight an important role of restricting the emergence of CTL immune escape variants in increasing the likelihood of PTC.