NK cells actively control HIV-1 DNA reservoir

The size of lentiviral DNA reservoirs reflects effectiveness of immune responses against lentiviruses. So far, abundant information has been gathered on the control of HIV-1 replication. Understanding of innate mechanisms contributing to containment of HIV-DNA reservoir, however, are only partly clarified and are relevant to guide interventions for reservoir containment or eradication. We studied the contribution of Natural Killer (NK) cell functional features in HIV patients either controlling replication either spontaneously (HIC) or after progression and antiretroviral treatment (PP). An inverse correlation between HIV-DNA copy numbers (either total or integrated) in circulating CD4+ cells and NK cell function were observed. Induced IFN-gamma production and NKp46/NKp30 activating receptor-induced expression correlated inversely with reservoir size. The correlation was present not only when considering a homogeneous cohort of HIC patients, but also when PP patients were included in the analysis. Adaptive (NKG2C + CD57 + ) NK cell features were not associated with reservoir size. However a distinct set of 370 differentially expressed transcripts was found to underlie functional differences in NK cells controlling HIV-DNA reservoir size. In proof-of-principle in vitro experiments of CD4+ cell infection with HIV-1, purified NK cells with the above functional/transcriptional features displayed a 10- and 30-fold higher ability to control HIV replication and DNA burden in vitro, respectively, compared to other NK cells. Thus, NK cells with a specific functional and transcriptional signature contribute to control of HIV reservoir in CD4+ cells. Their selection, expansion and/or adoptive transfer may support strategies to eradicate HIV-1 infection or to safely deescalate antiretroviral treatment.

16