IL-15 enhances HIV-1 infection by promoting survival and proliferation of CCR5⁺CD4⁺ T cells

HIV-1 usually utilizes CCR5 as its coreceptor and rarely switches to a CXCR4-tropic virus until the late stage of infection. CCR5⁺CD4⁺ T cells are the major virus-producing cells in viremic individuals as well as SIV-infected nonhuman primates. The differentiation of CCR5⁺CD4⁺ T cells is associated with the availability of IL-15, which increases during acute HIV-1 infection. Here, we report that CCR5 was expressed by CD4⁺ T cells exhibiting effector or effector memory phenotypes with high expression levels of the IL-2/IL-15 receptor common β and γ chains. IL-15, but not IL-7, improved the survival of CCR5⁺CD4⁺ T cells, drove their expansion, and facilitated HIV-1 infection in vitro and in humanized mice. Our study suggests that IL-15 plays confounding roles in HIV-1 infection, and future studies on the IL-15-based boosting of anti-HIV-1 immunity should carefully examine the potential effects on the expansion of HIV-1 reservoirs in CCR5⁺CD4⁺ T cells.