Circulating integrin α4 ß7+ CD4 T cells are enriched for proliferative transcriptional programs in HIV infection

Lakshmanappa, Yashavanth S; Roh, Jamin W; Rane, Niharika N; Dinasarapu, Ashok R; Tran, Daphne D; Velu, Vijayakumar; Sheth, Anandi N; Ofotokun, Igho; Amara, Rama R; Kelley, Colleen F; Waetjen, Elaine; Iyer, Smita S

HIV preferentially infects α4 ß7 + CD4 T cells, forming latent reservoirs that contribute to HIV persistence during antiretroviral therapy. However, the properties of α4 ß7 + CD4 T cells in blood and mucosal compartments remain understudied. Employing two distinct models of HIV infection, HIV-infected humans and simian-human immunodeficiency virus (SHIV)-infected rhesus macaques, we show that α4 ß7 + CD4 T cells in blood are enriched for genes regulating cell cycle progression and cellular metabolism. Unlike their circulating counterparts, rectal α4 ß7 + CD4 T cells exhibited a core tissue-residency gene expression program. These features were conserved across primate species, indicating that the environment influences memory T-cell transcriptional networks. Our findings provide an important molecular foundation for understanding the role of α4 ß7 in HIV infection.