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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244148 | GEO | 2025/12/09

REPOSITORIES: GEO

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Project description:The goal of this project is todetermine if natural killer (NK) cells could be able to control HIV replication and reduce or eliminate viral reservoirs leading to HIV cure or a functional cure. Despite thirty years of work and significant progress, HIV infection continues to be an incurable disease. Antiretroviral therapy (ART) has significantly decreased the morbidity and mortality, but lifelong treatment is merely suppressive and does not cure HIV/AIDS. This is because of the existence of a reservoir of viral DNA+ (vDNA+) in cells of the lymphoid tissues with an intact provirus that is thought capable of initiating new rounds of HIV replication (i.e. latency). In addition to this inducible reservoir data suggest ongoing low-level virus replication and persistence in lymphatic tissues of some patients that is related to suboptimal drug levels in these tissues. Strategies are needed that can address both issues. NK cells are innate immune effectors that recognize virally infected targets through a cadre of activating and inhibitory receptors but become dysfunctional in HIV infected people. Strikingly, African green monkeys (AGM) and sooty mangabeys mount a strong control of viral replication in lymph node follicles shortly after the viremia peak that lasts throughout infection. Several mechanisms have been proposed to be implicated in the strong control of viral replication in natural host’s lymph nodes, such as NK cell-mediated control. Indeed, we have recently shown that NK cells could migrate into the b cells follicles in a CXCR5 dependent manner and thus participate to the elimination of viral replication. Thus the purpose of this study is too compare at the transcriptomic level different subset of NK cell isolated from blood and peripheral lymph node of chronically infected AGM to identify a transcriptomic signature which could be linked to an efficient control of SIV replication. This results could then provide a new aproche which could be exploited to generate functional NK cells against HIV in infected patients.

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

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