IL-15 promotes activation and expansion of [CD8.sup.+] T cells in HIV-1 infection

In HIV-1-infected patients, increased numbers of circulating [CD8.sup.+] T cells are linked to increased risk of morbidity and mortality. Here, we identified a bystander mechanism that promotes CD8 T cell activation and expansion in untreated HIV-1-infected patients. Compared with healthy controls, untreated HIV-1-infected patients have an increased population of proliferating, granzyme [B.sup.+], [CD8.sup.+] T cells in circulation. Vβ expression and deep sequencing of CDR3 revealed that in untreated HIV-1 infection, cycling memory CD8 T cells possess a broad T cell repertoire that reflects the repertoire of the resting population. This suggests that cycling is driven by bystander activation, rather than specific antigen exposure. Treatment of peripheral blood mononuclear cells with IL-15 induced a cycling, granzyme [B.sup.+] phenotype in [CD8.sup.+] T cells. Moreover, elevated IL-15 expression in the lymph nodes of untreated HIV-1-infected patients correlated with circulating [CD8.sup.+] T cell counts and was normalized in these patients following antiretroviral therapy. Together, these results suggest that IL-15 drives bystander activation of [CD8.sup.+] T cells, which predicts disease progression in untreated HIV-1-infected patients and suggests that elevated IL-15 may also drive [CD8.sup.+] T cell expansion that is linked to increased morbidity and mortality in treated patients.