Scientists have narrowed in on a group of gut-residing immune cells that might predispose women to increased HIV infection risk and more severe disease. The findings suggest already-existing treatments for inflammatory bowel disease could be repurposed as valuable interventions for HIV, they say. Researchers have long recognized that immune cells in the gut (an area of the body thought to act as a major viral reservoir) play critical roles in HIV infection, and the ability of T cells to navigate from the bloodstream to the intestine depends on a protein called integrin α4β7. By examining blood samples obtained from a group of high-HIV risk women in KwaZulu-Natal, South Africa before they acquired the virus, Aida Sivro and colleagues determined that elevated frequencies of α4β7-expressing T cells correlated with increased infection risk. Similar associations between bloodstream levels of α4β7-expressing T cells and HIV risk were also observed among cohorts of women sex-workers in Kenya. Among women who became infected, elevated proportions of α4β7-expressing T cells correlated with higher HIV viral loads and more rapid T cell decline (hallmarks of severe disease). Importantly, elevated blood levels of α4β7-expressing T cells corresponded to increased frequencies of these cells in the urogenital tract, hinting at a possible route for the virus to take hold. Sivro et al. observed similar trends in experimental SIV infections in nonhuman primates. The authors speculate that α4β7-expressing T cells might be one of the first targets that the HIV virus infects, and zeroing in on these cells could be valuable for prevention or treatment.