Multi-omics analyses reveal that HIV-1 alters CD4+ T cell immunometabolism to fuel virus replication

Individuals infected with human immunodeficiency virus type-1 (HIV-1) show metabolic alterations of CD4(+) T cells through unclear mechanisms with undefined consequences. We analyzed the transcriptome of CD4(+) T cells from patients with HIV-1 and revealed that the elevated oxidative phosphorylation (OXPHOS) pathway is associated with poor outcomes. Inhibition of OXPHOS by the US Food and Drug Administration-approved drug metformin, which targets mitochondrial respiratory chain complex-I, suppresses HIV-1 replication in human CD4(+) T cells and humanized mice. In patients, HIV-1 peak viremia positively correlates with the expression of NLRX1, a mitochondrial innate immune receptor. Quantitative proteomics and metabolic analyses reveal that NLRX1 enhances OXPHOS and glycolysis during HIV-1-infection of CD4(+) T cells to promote viral replication. At the mechanistic level, HIV infection induces the association of NLRX1 with the mitochondrial protein FASTKD5 to promote expression of mitochondrial respiratory complex components. This study uncovers the OXPHOS pathway in CD4(+) T cells as a target for HIV-1 therapy. Ting and colleagues use multi-omics to examine the alterations undergone by CD4(+) T cells following HIV-1 infection. They describe mechanistic changes that lead to elevated oxidative phosphorylation, which, if inhibited, leads to suppression of HIV-1 infection.

Automated summary

Researchers have found that HIV-1 infection leads to metabolic changes in CD4(+) T cells, with the OXPHOS pathway associated with poor outcomes and NLRX1 promoting viral replication. Inhibiting mitochondrial respiratory complex-I can suppress HIV-1 replication.