Cellular Metabolism Is a Major Determinant of HIV-1 Reservoir Seeding in CD4+ T Cells and Offers an Opportunity to Tackle Infection

• Published in: Cell metabolism 2019-03, Vol.29 (3), p.611-626.e5
• Main Authors: Valle-Casuso, José Carlos, Angin, Mathieu, Volant, Stevenn, Passaes, Caroline, Monceaux, Valérie, Mikhailova, Anastassia, Bourdic, Katia, Avettand-Fenoel, Véronique, Boufassa, Faroudy, Sitbon, Marc, Lambotte, Olivier, Thoulouze, Maria-Isabel, Müller-Trutwin, Michaela, Chomont, Nicolas, Sáez-Cirión, Asier
• Format: Article
• Language: English
• Subjects: CD4+ T cell; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; Cell Differentiation; Cells, Cultured; cellular metabolism; glycolysis; Glycolysis - immunology; HIV Infections - metabolism; HIV Infections - pathology; HIV reservoir; HIV-1; Humans; Immunology; Life Sciences; Lymphocyte Activation; metabolic inhibitors; Microbiology and Parasitology; Oxidative Phosphorylation; susceptibility to HIV-1; T cell differentiation; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets - pathology; Virology
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2018.11.015

HIV persists in long-lived infected cells that are not affected by antiretroviral treatment. These HIV reservoirs are mainly located in CD4+ T cells, but their distribution is variable in the different subsets. Susceptibility to HIV-1 increases with CD4+ T cell differentiation. We evaluated whether the metabolic programming that supports the differentiation and function of CD4+ T cells affected their susceptibility to HIV-1. We found that differences in HIV-1 susceptibility between naive and more differentiated subsets were associated with the metabolic activity of the cells. Indeed, HIV-1 selectively infected CD4+ T cells with high oxidative phosphorylation and glycolysis, independent of their activation phenotype. Moreover, partial inhibition of glycolysis (1) impaired HIV-1 infection in vitro in all CD4+ T cell subsets, (2) decreased the viability of preinfected cells, and (3) precluded HIV-1 amplification in cells from HIV-infected individuals. Our results elucidate the link between cell metabolism and HIV-1 infection and identify a vulnerability in tackling HIV reservoirs. [Display omitted] •The susceptibility of CD4+ T cell subsets to HIV-1 matches their metabolic activity•HIV-1 selectively infects CD4+ T cells with enhanced glycolysis and OXPHOS•Inhibition of metabolic activities blocks HIV-1 replication•Suboptimal inhibition of glycolysis impairs amplification of HIV-1 reservoirs Targeting HIV reservoirs remains a challenge. Valle-Casuso et al. found that HIV-1 selectively infects highly metabolic CD4+ T cells, independent of their activation phenotype. Inhibition of metabolic pathways blocks the early steps of HIV-1 replication and induces death of infected cells, highlighting a metabolic vulnerability that can be therapeutically exploited.