Sex differences in HIV-1 reservoir cell selection are linked to altered innate immune profiles

HIV-1 persistence despite suppressive antiretroviral therapy (ART) is primarily because of infected memory CD4 T cells, so-called viral reservoir cells, that harbor chromosomally integrated viral DNA as a "provirus" and resist clearance by the human immune system. Biological sex affects host immune responses and may influence selection and evolution of HIV-1 reservoir cells during long-term ART for HIV infection. We assessed more than 4073 individual proviruses through single-molecule amplification from 30 females and 35 males living with HIV-1 and treated with ART for a median of 20 years. We observed that the HIV-1 reservoir profile in females was characterized by lower proviral phylogenetic complexity, an increased proportion of clonally expanded intact proviruses, and a higher proportion of intact proviruses integrated into repressive heterochromatin locations of the human genome. The evolution of this distinct viral reservoir profile in females was associated with an improved signature of innate immune responses, specifically those of NK cells. On the contrary, signs of viral sequence adaptation to adaptive T cell immune responses were more pronounced in intact HIV-1 proviruses from males. Collectively, these data suggest a stronger ability of the female immune system to drive immune selection of HIV-1 reservoir cells during ART, putatively because of improved innate immune function.