Natural Killer Cells and their Role in Preventing HIV-1 Transmission

Abstract

Despite the enormous efficacy of HIV-1 transmission resulting in a worldwide epidemic, the virus is extremely vulnerable in the brief period between initial HIV-1 exposure and establishment of systemic infection with most HIV-1 infections being prematurely abrogated by the innate immune defenses of the human host. Evidence is accumulating that natural killer (NK) cells play an important role in mediating this innate resistance to HIV-1 infection. NK cells are innate lymphocytes in the first line of defense against viruses capable of rapidly killing virus-infected cells without prior sensitization. NK cells also modulate the ensuing adaptive immune responses by releasing cytokines and promoting dendritic cell maturation. Genetic studies of highly HIV-exposed but seronegative (HESN) subjects consistently showed that these individuals are enriched for NK cell receptor repertoires with an NK cell-activating profile. While functional studies of NK cells are starting to unravel the mechanisms behind these genetic associations, ex vivo analyses frequently identified signatures of activated NK cells in HESN individuals. Recent investigations of the mucosal genital immune environment, however, show that protection against HIV-1 infection depends on a delicate balance of protective and detrimental consequences of innate immune activation and of NK cells in particular. Further research will have to unravel the specific components of this balance before seeking to apply the HIV-1 preventive potential of NK cells in immune-based medical interventions.