Accumulation of CXCR5+ NK cells during chronic SHIV infection is associated with enhanced viral control

Abstract

Abstract Natural Killer (NK) cells play an essential role in antiviral immunity, however knowledge pertaining to their function in lymphoid organs during chronic HIV infection is not clearly elucidated. Lymph node (LN) follicles constitute major reservoir sites for HIV persistence. Cure strategies could benefit from the LN CXCR5+ NK cells able to access/eliminate viral reservoirs. Here we studied the phenotype, distribution and function of CXCR5+ NK cells in the LN of SHIV naive and chronic SHIV-infected (>14 weeks PI) rhesus macaques (RM) and its association with plasma viral RNA levels. We found that prior to infection, a significant proportion of NK cells (~15%) expressed CXCR5. Following infection, the frequency of CXCR5+ NK cells was significantly higher in chronic SHIV-infected RM. Phenotypically CXCR5+ NK cells express higher levels of CD32a and CD16 compared to CXCR5− cells, which might be important for ADCC function. RNA expression profiling of sorted CXCR5+ and CXCR5− NK cells from LNs of chronic SHIV-infected RM revealed that CXCR5+ cells are activated and express increased levels of cytolytic markers (perforin, granzyme-B, granulysin and CD107a), suggesting that these cells have a higher capacity to kill. Gene set enrichment analysis showed elevated expression in CXCR5+ cells of transcripts associated with cell activation, TNF-alpha, Interferon signaling and apoptosis. Importantly, the higher frequency of CXCR5+ NK cells was associated with lower SHIV plasma viral RNA levels and lower germinal center Tfh cells. Thus these data suggest that CXCR5+ NK cells could play an important role in controlling chronic SHIV infection. HIV cure strategies should focus on inducing CXCR5+ NK cells that may contribute to sustained viral remission.