Induction of Resident Memory CD8 ⁺ T cell Phenotypes to Eliminate the HIV reservoir

Enhancing effective antiviral responses within tissue compartments supporting HIV persistence at the time of antiretroviral therapy interruption will be necessary to limit viral rebound. With the hypothesis that CD8 ⁺ tissue resident memory T cell (T _RM ) phenotypes might be more competent at controlling tissue viral recrudescence, we examined their capacity to control HIV after reactivation and the benefit of inducing T _RM -like phenotypes through cytokine stimulation from blood. CD8 ⁺ T _RM derived from cervical tissue were more efficient at eliminating reactivated HIV-infected CD4 ⁺ T cells compared to circulating effector CD8 ⁺ T cells. Expansion of CD8 ⁺ T _RM -like phenotypes from blood through IL-15/TGF-β1 stimulation recovered functional HIV-specific CD8 ⁺ T cells displaying residency features, increased clonotypic diversity and mitochondrial function, and were the most efficient phenotypes at eliminating intact viruses after reactivation. Altogether, we provide a relevant therapeutic strategy to enhance elimination of persistent antigens like HIV by generating functional CD8 ⁺ T _RM -like phenotypes.