Quantifying Virus Escape from T Cells in the Latent HIV Reservoir

Abstract There is no cure for HIV, largely because HIV establishes a small but sustained pool of latently infected cells that are not cleared by antiretroviral therapy (ART). Current strategies include firstly reactivating the latent HIV reservoir and then using T cell immunotherapy to clear reactivated cells. However, pre-ART CD8 T cell escape variants have been reported in the HIV reservoir, which may limit CD8 T cell recognition and clearance of HIV-infected cells. The extent of virus escape from T cells in the latent reservoir is unclear. HIV-specific T cell responses were comprehensively mapped across the Clade B HIV proteome by IFN-g ELISpot in 25 ART-suppressed participants. In parallel, replication competent viruses derived from supernatants of autologous resting CD4 T cells following mitogenic reactivation were sequenced. Peptides spanning virus variants within reactive T cell epitopes were synthesized and examined by ELISpot for evidence of escape, defined as ≥50% difference in T cell magnitude between peptide variants. No correlations were observed between the size of the latent HIV reservoir and either HIV-specific T cell breadth (1–19 epitopes) or magnitude (156–2855 SFU/M PBMCs). T cell escape was assessed in 17 participants. 39% of reactive T cell epitopes (48/124) harbored ≥1 amino acid variants in the sequenced latent reservoir. Of those 48, 20 afforded T cell escape, providing an overall escape frequency in the reservoir of 16% (20/124). These data show that the majority of replication competent latent HIV viruses do not harbor CD8 T cell escape mutants, suggesting that immunotherapy approaches that boost CD8 T cell responses can successfully target the latent reservoir in HIV curative and or remission strategies.