HIV-1-induced cytokines deplete homeostatic innate lymphoid cells and expand TCF7-dependent memory NK cells

HIV-1 infection is associated with heightened inflammation and excess risk of cardiovascular disease, cancer, and other complications. These pathologies persist despite antiretroviral therapy (ART). In two independent cohorts, we found that innate lymphoid cells (ILCs) were depleted in the blood and gut of people with HIV-1, even with effective ART. ILC depletion was associated with neutrophil infiltration of the gut lamina propria, type 1 interferon activation, increased microbial translocation, and natural killer (NK) cell skewing towards an inflammatory state with chromatin structure and phenotype typical of WNT transcription factor TCF7-dependent memory T cells. Cytokines that are elevated during acute HIV-1 infection reproduced the ILC and NK cell abnormalities ex vivo. These results demonstrate that inflammatory cytokines associated with HIV-1 infection irreversibly disrupt ILCs. This results in loss of gut epithelial integrity, microbial translocation, and memory NK cells with heightened inflammatory potential, and explains the chronic inflammation in people with HIV-1.