IL-15 drives CD8 T cell cycling and differentiation in chronic HIV-1 infection (VIR6P.1162)

HIV-1 infection is characterized by sustained CD8 T cell expansion that is linked to morbid outcomes even after HIV replication is controlled with antiretroviral therapy (ART). The drivers of this persistent CD8 expansion in HIV-1 infection are not well understood. Here we show that cycling frequency is increased in memory CD8 T cells in untreated HIV-1 infected patients and cycling CD8 T cells have a broad T cell receptor repertoire tightly linked to the repertoire of non-cycling cells suggesting that they are largely driven into cycle by bystander mechanisms. In HIV-1 infection, cycling and granzyme B expression were increased among CD8 T cells binding viral peptide/HLA tetramers and this enriched cycling/cytolytic phenotype among virus-reactive CD8 T cells could be generated in vitro by exposure to interleukin (IL)-15. Lymph nodes of HIV-1 infected untreated patients were enriched for interleukin-15 expression that correlated with circulating CD8 T cell counts and normalized with drug-induced control of HIV-1 replication. The determinants of persistent CD8 T cell expansion and the mechanisms whereby this expansion is linked to increased morbidity merit further examination.