BACKGROUND: Rare individuals, termed HIV post-treatment controllers (PTCs), can exhibit prolonged periods of viral control upon ART withdrawal, but the mechanisms by which this occurs remain poorly understood. In this study, we assessed whether PTCs exhibit unique T-cell properties.
METHODS: A 40-parameter CyTOF panel was developed to characterize the differentiation, activation, and other phenotypic features of T cells. The panel was applied to PBMCs collected on ART and prior to treatment interruption from clinically matched PTC (n=20) and non-controller (NC) participants (n=32). In addition, post-interruption specimens were analyzed to characterize differential features between PTCs and NCs off ART. CyTOF datasets were gated on T cells, and clustered and mixed effects models were used to identify associations with PTC/NC status.
RESULTS: By implementing cluster-resolution optimization, we identified nine distinct T cell clusters. Prior to ART interruption, one cluster was significantly less abundant in subsequent PTCs than NCs. This cluster consisted of memory CD8+ T cells expressing high levels of PD1 and TIGIT, suggesting immune exhaustion. After ART interruption, a separate cluster comprised predominantly of activated CD8+ Temra cells expressing high levels of the pro-survival factor BIRC5 significantly increased in abundance in PTCs, while it exhibited the opposite pattern in NCs. We also found post-ART that NCs harbored a larger proportion of a cluster that was comprised of CD4-CD8- T cells expressing high levels of Tfh marker CXCR5 and activation marker CD30, both previously shown to be increased on HIV-infected cells.
CONCLUSIONS: Our data suggest that prior to interrupting ART, people who subsequently control HIV exhibit lower frequencies of exhausted CD8+ T cells, which may enable these individuals to better control HIV replication upon ART cessation. After ART interruption, a population of activated CD8+ Temra expressing BIRC5 expands in PTCs but not NCs; theoretically, these cells might persist longer and be able to maintain more direct virus control. Post-ATI viremia in NCs is associated with a population of CD4-CD8- T cells expressing antigens associated with HIV-infected cells; ongoing work seeks to determine whether these cells are productively-infected with HIV.

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