Highly dampened HIV-specific cytolytic effector T cell responses define viremic non-progression

This study reports on HIV-specific T cell responses in HIV-1 infected Viremic Non-Progressors (VNPs), a rare group of people living with HIV that exhibit asymptomatic infection over several years accompanied by stable CD4+ T cell counts in spite of ongoing viral replication. We attempted to identify key virus-specific functional attributes that could underlie the apparently paradoxical virus-host equilibrium observed in VNPs. Our results revealed modulation of HIV-specific CD4+ and CD8+ effector T cell responses in VNPs towards a dominant non-cytolytic profile with concomitantly diminished degranulation (CD107a+) ability. Further, the HIV specific CD8+ effector T cell response was primarily enriched for MIP-1β producing cells. As expected, concordant with better viral suppression, VCs exhibit a robust cytolytic T cell response. Interestingly, PuPs shared features common to both these responses but did not exhibit a CD4+ central memory IFN-γ producing Gag-specific response that was shared by both non-progressor (VC and VNP) groups, suggesting CD4 helper response is critical for non-progression. Our study also revealed that cytolytic response in VNPs is primarily limited to polyfunctional cells while both monofunctional and polyfunctional cells significantly contribute to cytolytic responses in VCs. To further understand mechanisms underlying the unique HIV-specific effector T cell response described here in VNPs we also evaluated and demonstrated a possible role for altered gut homing in these individuals. Our findings inform immunotherapeutic interventions to achieve functional cures in the context of ART resistance and serious non AIDS events.