CD8ɑ+ cells suppress SIV replication without the development of mutations within MHC class-I-restricted epitopes during post-treatment control.

Post-treatment control (PTC) is a rare phenomenon in which people living with HIV (PLWH) maintain viral control following antiretroviral treatment (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 (MCMs) were infected with barcoded SIVmac239M and began an 8-month ART regimen 2 weeks post-infection (wpi). Six months following ART interruption, all MCMs were rechallenged with non-barcoded SIVmac239, followed by CD8α+ cell depletion 2 months later. Animals were grouped as viremic ( IMPORTANCE: While rare, a subset of PLWH, termed post-treatment controllers (PTCs), maintains viral control following antiretroviral treatment (ART) interruption. However, little is known about whether this control reflects a complete absence of viral replication or continual, subclinical replication. Here, we address a key knowledge gap regarding how viral populations change during CD8ɑ+ cell-mediated PTC of SIV. We utilized our Mauritian cynomolgus macaque model of HIV infection, in combination with barcoded SIVmac239M and deep sequencing, to characterize viral lineages and MHC-I-restricted CD8+ T-cell epitopes throughout the study. Our findings demonstrate that early ART initiation limits viral diversity, that pre-ART replication predicts post-ART reactivation, and that CD8ɑ+ cells can suppress viral replication without the emergence of mutations within CD8+ T-cell epitopes. These insights establish MCMs as a valuable model for dissecting mechanisms of durable ART-free viral control and highlight the potential of CD8-mediated immune control as a therapeutic target for HIV cure strategies.