Pomalidomide as an immune-enhancing agent in samples from people living with HIV

Persisting immune dysfunction in people living with HIV (PLHIV) on suppressive antiretroviral therapy (ART) is a key challenge to finding a cure for HIV. We investigated pomalidomide, a well-tolerated immunomodulatory drug, as an agent to enhance HIV-directed immune responses. We collected peripheral blood mononuclear cells (PBMC) from PLHIV on ART, cultured these in the presence of HIV peptides and found that pomalidomide significantly expanded tetramer-positive HIV-specific CD8+ T-cells with reduced markers of exhaustion and enhanced CD8+ T-cell-mediated killing of HIV-target cells. This was associated with an upregulation of carbon metabolism and cell cycle pathways, with MYB and BATF3 implicated as key regulators of the pomalidomide-mediated response. Pomalidomide also enhanced NK cell cytotoxicity against K562 as well as HIV-infected target cells by expanding polyfunctional cytotoxic NK cells. Given its immune-enhancing potential and good safety profile, pomalidomide should be further investigated as a therapeutic strategy for HIV control and cure. Overall design: PBMC from six people living with HIV on suppressive ART were exposed to HIV antigen and treated with either DMSO or pomalidomide (0.25 uM) for 13 days. MHC-I:HIV peptide tetramers were used to isolate HIV-specific CD8+ T cells, and cells were sequenced using Illumina TruSeq.