NK Response Correlates with HIV Decrease in Pegylated IFN-α2a-Treated Antiretroviral Therapy-Suppressed Subjects

We previously reported that pegylated IFN-alpha 2a (Peg-IFN-alpha 2a) added to antiretroviral therapy (ART)-suppressed, HIV-infected subjects resulted in plasma HIV control and integrated HIV DNA decrease. We now evaluated whether innate NK cell activity or PBMC transcriptional profiles were associated with decreases in HIV measures. Human peripheral blood was analyzed prior to Peg-IFN-alpha 2a administration (ART, baseline), after 5 wk of ART+ Peg-IFN-alpha 2a, and after 12 wk of Peg-IFN-alpha 2a monotherapy (primary endpoint). After 5 wk of ART+ Peg-IFN-alpha 2a, immune subset frequencies were preserved, and induction of IFNstimulated genes was noted in all subjects except for a subset in which the lack of IFN-stimulated gene induction was associated with increased expression of microRNAs. Viral control during Peg-IFN-alpha 2a monotherapy was associated with 1) higher levels of NK cell activity and IFN-g-induced protein 10 (IP-10) on ART (preimmunotherapy) and 2) downmodulation of NK cell KIR2DL1 and KIR2DL2/DL3 expression, transcriptional enrichment of expression of genes associated with NK cells in HIV controller subjects, and higher ex vivo IFN-alpha-induced NK cytotoxicity after 5 wk of ART+ Peg-IFN-alpha 2a. Integrated HIV DNA decline after immunotherapy was also associated with gene expression patterns indicative of cell-mediated activation and NK cytotoxicity. Overall, an increase in innate activity and NK cell cytotoxicity were identified as correlates of Peg-IFN-alpha 2a-mediated HIV control.