Retinoids enhance NK effector function against HIV-infected CD4 T cells

Novel approaches to sensitize latently infected cells to apoptosis may provide additional methods to eliminate latent reservoirs. Prior research identified several retinoids as potential drugs that increase the sensitivity of HIV-infected cells to cell death. Retinoids are derivatives of vitamin A that target retinoid receptors causing antiproliferative and proapoptotic activity. Several are FDA-approved or in clinical trials. The aim of this study was to evaluate the ability of vitamin A, three of its natural metabolites, and nine synthetic derivatives to sensitize HIV-infected CD4 T cells to NK natural cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC). From the retinoids tested, alitretinoin, tazarotene acid, and AM80 significantly enhanced NK natural cytotoxicity in the presence of IL-15. Mechanistically, these retinoids increased NK degranulation upon target recognition in an HLA-F/KIR3DS1-dependent manner. Furthermore, these retinoids enhanced ADCC by transcriptionally increasing CD16 expression on NK cells. In conclusion, our study has identified at least three retinoids capable of enhancing NK natural cytotoxicity and ADCC against HIV-infected cells. These or other retinoids could be used to reduce HIV persistent reservoirs.IMPORTANCEThis study highlights how retinoids, compounds derived from vitamin A, can help the immune system target HIV-infected cells more effectively. HIV often hides in immune cells, making it difficult to fully eliminate the virus. We found that certain retinoids, including alitretinoin, tazarotene acid, and AM80, improve the function of natural killer (NK) cells-key immune cells that target infected cells. These retinoids boost NK cell activity by increasing their ability to release toxic molecules that kill infected cells and by enhancing their response to antibodies targeting HIV. This makes the infected cells more vulnerable to being eliminated. Since some of these retinoids are already approved for medical use, they could offer a promising way to reduce persistent HIV reservoirs in the body and improve efforts to cure the infection.