Pomalidomide enhances CD8⁺ T and NK cell mediated killing of HIV-infected cells.

Abstract

Overcoming persisting immune dysfunction in people living with HIV (PLHIV) on suppressive antiretroviral therapy (ART) is a key challenge to curing HIV. Agents that reverse immune dysfunction may enhance viral immunity to support the immunological control and clearance of persisting HIV as part of curative strategies. Here, 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 cells in the presence of HIV peptides and pomalidomide or DMSO control, and profiled the proliferative and cytotoxic functionality, and transcriptional landscape of HIV-specific CD8⁺ T-cells using MHC-I:HIV-peptide tetramers. Ex vivo pomalidomide-treated NK cells from PLHIV were also immunophenotyped, and assessed for polyfunctionality, ligand-mediated cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) against HIV-expressing target cells. Our findings demonstrated that pomalidomide significantly expanded tetramer-positive HIV-specific CD8⁺ T-cells with reduced markers of exhaustion, resulting in enhanced CD8⁺ T-cell-mediated killing of HIV-target cells. The expansion of CD8⁺ T-cells was associated with an upregulation of carbon metabolism and cell cycle pathways, with MYB and BATF3 key regulators of the pomalidomide-mediated response. Pomalidomide also enhanced NK cell killing of the human erythroleukemia K562 cell line and HIV-infected target cells by expanding polyfunctional cytotoxic NK cells with reduced TIGIT expression. Given the immune-enhancing effects and excellent safety profile, pomalidomide should be further investigated as an immune-enhancing strategy for an HIV cure. This study was supported by grants from the National Health and Medical Research Council of Australia (NHMRC), The Australian Centre for HIV and Hepatitis Research (ACH4), the Melbourne HIV Cure Consortium, J & M Wright Foundation, Australia, and the Independent Research Fund, Denmark.