Integrative transcriptomic and proteomic analyses reveal that NLRX1 and FASTDK5 orchestrate immunometabolic fitness to fuel HIV-1 replication

We analyzed the transcriptome of CD4 T cells from HIV-1 patients and revealed that elevated oxidative phosphorylation (OXPHOS) pathway is associated with poor outcomes. Inhibition of OXPHOS by the FDA-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 levels, HIV infection induces the association of NLRX1 with the mitochondrial protein, FASTKD5, to promote the expression of mitochondrial respiratory complexes components. This study uncovers the OXPHOS pathway in CD4 T cells as an un-appreciated target for HIV-1 therapy. Cells were collected and lysed for RNA extraction. Reverse transcription reactions were performed to obtain cDNAs which were hybridized to the Illumina Human HT-12 version 4 Expression BeadChip according to the manufacturer’s instruction, and quantified using an Illumina iScan System. The data were collected with Illumina GenomeStudio software.