Resident memory T cells are a cellular reservoir for HIV in the cervical mucosa

HIV viral reservoirs are established very early during infection. Resident memory T cells (T_RM) are present in tissues such as the lower female genital tract, but the contribution of this subset of cells to the pathogenesis and persistence of HIV remains unclear. Here, we show that cervical CD4⁺T_RM display a unique repertoire of clusters of differentiation, with enrichment of several molecules associated with HIV infection susceptibility, longevity and self-renewing capacities. These protein profiles are enriched in a fraction of CD4⁺T_RM expressing CD32. Cervical explant models show that CD4⁺T_RM preferentially support HIV infection and harbor more viral DNA and protein than non-T_RM. Importantly, cervical tissue from ART-suppressed HIV⁺ women contain high levels of viral DNA and RNA, being the T_RM fraction the principal contributor. These results recognize the lower female genital tract as an HIV sanctuary and identify CD4⁺T_RM as primary targets of HIV infection and viral persistence. Thus, strategies towards an HIV cure will need to consider T_RM phenotypes, which are widely distributed in tissues.