A major challenge in the development of HIV curative strategies is the formation of viral reservoirs that are not eradicated with antiretroviral therapy (ART). Understanding mechanisms that determine HIV reservoir size may inform development of effective cure approaches. As natural killer (NK) cells may contribute to control of HIV infection, we hypothesized that NK cells may affect reservoir size.
To evaluate the association between NK cells and HIV reservoir, we used mass cytometry to profile NK cells from 50 people with HIV on suppressive ART in AIDS Clinical Trials Group study A5321. NK cell repertoire was assessed at time of study entry (median of 7.1 years after ART initiation) and 24 and 48 weeks later. Prior to ART initiation, one year following ART initiation, and at study entry, we assessed inflammatory markers and markers of HIV persistence (cell-associated DNA (CA-DNA), cell-associated RNA and HIV RNA by single copy assay). T cell responses to peptide pools were assessed at study entry.
In participants on chronic ART, the NK cell repertoire was stable as assessed by expression patterns of NK cell activation and differentiation markers at study entry, week 24, and week 48. At study entry, there was no significant correlation between on-ART NK cell diversity and any of the on-ART HIV reservoir measures. We next evaluated whether NK cell features, inflammatory markers, or T cell responses can explain the reduction in log10-transformed HIV DNA levels between the pre-ART time point and one year post ART initiation (CA-DNA reduction). We performed a supervised multivariate regression using the least absolute shrinkage and selection operator (LASSO). This approach selected the expression of perforin, CD38, 2B4, TIGIT, and CD96 on NK cells and the T cell response to “nef, tat, rev” peptide pools as the best explanatory variables for the prediction of CA-DNA reduction (see Table).
Here we show that specific NK cell marker expression levels and T cell responses can be used as explanatory variables in the regression analysis of the decline in HIV DNA levels following ART initiation. These observations suggest that specific NK cell features may drive an enhanced response to infected cells in the context of treatment initiation. Harnessing this potential may lead to the development of novel therapeutic strategies aimed at a functional cure for HIV.