HIV-1-mediated induction of Hypoxia Inducible Factor-1 alpha activity in CD4+ T cells modifies immunometabolic phenotype and decreases cell survival.

PALMER, CLOVIS S.; VARESE, AUGUSTO; GERBER, PEHUÉN PEREYRA; RUBIONE, JULIA; OSTROWSKI, MATIAS; DÍAZ, FERNANDO ERRA; DUETTE, GABRIEL

París

Congreso; 9th IAS Conference on HIV Science; 2017

International AIDS Society

Background: Chronic T cell activation and dysfunction are hallmarks of HIV infection. Taking into consideration that T cell metabolism influences T cell functionality, we hypothesized that CD4+T cell dysfunction during HIV infection could be associated to virus-induced metabolic alterations. A critical transcription factor in the coordination of T cell metabolism, differentiation and effector function is Hypoxia Inducible Factor-1α (HIF-1α). Herein, we analyzed the expression, activity and function of HIF-1α in CD4+T cells.Methods: CD4+T cells isolated from the blood of healthy donors were activated with anti-CD3/CD28 antibodies and infected in vitro with HIV. HIF-1α activity was evaluated by using a reporter cell line, expressing GFP under the control of the Hypoxia-Responsive-Element. Cytokine production was evaluated by CBA kit. Cell viability was evaluated by 7-AAD staining and Annexin V binding. Silencing of HIF-1α expression was achieved by transduction with lentivirus-encoded shRNAs. To analyze ex vivo the relationship between HIF-1α levels and cell death in CD4+T cells a total of 7 HIV-1-infected patients on cART and 6 healthy donors were recruited.Results: We show that HIV-1 infection triggers HIF-1α expression and activity, promoting aerobic glycolysis and the production of proinflammatory cytokines in CD4+T cells infected in vitro. We also observed that the promotion of aerobic glycolysis by HIV is associated with a higher rate of CD4+T cell death. Remarkably, silencing HIF-1α expression in CD4+T cells reverted the promotion of cell death and production of proinflammatory cytokines induced by HIV-1 infection. Finally, we also analyzed HIF-1α expression in samples from HIV-1-infected patients on cART. Interestingly, these patients also exhibit higher levels of HIF-1α expression compared to healthy donors. Moreover, the expression levels of this transcription factor presented a negative correlation with CD4+T cell counts.Conclusions: In conclusion, we show that HIV infection induces the activity of HIF-1α in productively infected cells promoting glycolytic activity, a proinflammtory phenotype and cell death. These results pave the way to explore the possibility of targeting HIF-1α and/or T cell metabolism to restore CD4+T cell physiology in HIV-1 infected individuals