A natural talent: natural killer cells in nonpathogenic Simian immunodeficiency virus infection

PURPOSE OF REVIEW: HIV emerged from simian immunodeficiency virus (SIV), which infects African nonhuman primates (NHP). Among these natural hosts of SIV, some species are characterized by lack of progression toward AIDS, despite persistent high viremia. Most recently, natural killer (NK) cells have emerged as an important mechanism by which natural hosts avoid pathogenesis. This review summarizes the findings on NK cells in natural hosts, with a particular focus on recent findings in African green monkeys (AGMs); the discovery of novel functions of NK cells; and lessons learned for the development of an HIV cure. RECENT FINDINGS: AGMs display strong control of SIV replication in secondary lymphoid organs, unlike humans living with HIV-1. This control is mediated by NK cells and favored through high levels of membrane-bound trans-presentation of interleukin-15 (mbIL-15) by follicular dendritic cells, migration into B cell follicles by IL-6-mediated CXCR5 upregulation, and expansion of terminally differentiated NKG2AlowCD16+ NK cells with increased MHC-E restricted activity and enhanced potential for antibody-dependent cellular cytotoxicity. SUMMARY: Study of SIV natural hosts has identified protective immune mechanisms with potential therapeutic applications for HIV cure.