IL-15 Enhances HIV-1 infection by Promoting Differentiation and Survival of CCR5+CD4+ T cells

HIV-1 usually utilize CCR5 as the co-receptor and rarely switches to CXCR4-tropic until late stage of infection. CCR5+CD4+ T cells are the major virus-producing cells in patients as well as SIV-infected non-human 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 is expressed by CD4+ T cells exhibiting effector or effector memory phenotype with high expression levels of the IL-2/IL-15 receptor common beta and gamma chains. IL-15 but not IL-7 improves the survival of CCR5+CD4+ T cells, drives their expansion, and facilitates 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 exam the potential effects on the expansion of HIV-1 reservoirs in CCR5+CD4+ T cells. Overall design: Human primary CD4+ T cells were purified by negative selection with MojoSort™ Human CD4 T Cell Isolation Kit (Biolegend) or EasySep™ Human CD4+ T Cell Isolation Kit (Stem Cell Technology). Purified CD4+ T cells (106 cells/mL) were cultured in RPMI 1640 medium supplemented with 10% FCS, penicillin (100 unit/mL) and streptomycin (100 µg/mL). To generate activated cells, CD4+ T cells were stimulated with plate-bound anti-CD3 and anti-CD28 antibodies at 1µg/mL (BioLegend) for 3 days in the presence of 20 ng/mL IL-2. Stimulated CD4+ T cells were cultured with 20 ng/mL IL-7 or IL-15. Fresh medium was provided every 3 days to keep the cell densities at 1-2*106 cells/mL. Activated blood CD4+ T cells were cultured with the presence of IL-15 for 6 days. CCR5+ and CCR5- CD4+ T cells were sorted followed by bulk RNA-Seq experiments.