NLRX1 Facilitates HIV-1 Infection of CD4 T Cells by Promoting Oxidative Phosphorylation

Abstract

Abstract The nucleotide-binding, leucine-rich-repeat-containing protein, NLRX1 is recognized as a host factor which promotes HIV-1 infection of myeloid cells by suppressing HIV-1 reverse transcribed DNA induced and STING-mediated innate immune response. However, the function of NLRX1 in HIV-1 infection of CD4 T cells, the major cells responsible for HIV-1 replication in vivo, is still unrevealed. Here we found NLRX1 still acted as a host factor required for HIV-1 infection of the human T cell line, primary CD4 T cells, and CD4 T cell-reconstituted humanized mice through a mechanism involved in cell intrinsic pathways but not innate immune cytokines. In the perspective of virology, we found NLRX1 facilitated both of the integration of HIV-1 cDNA and HIV-1 LTR-mediated viral gene transcription. By using SILAC-based quantitative proteomics, we characterized that HIV-1 infection-induced expression of genes involved in the electron transport chain (ETC) of mitochondria through an NLRX1 dependent mechanism. Consistent with the proteomics data, HIV-1 infection led to increased oxidative phosphorylation in Jurkat T cell line but not in the counterpart containing shRNAs against NLRX1. In addition, inhibition of oxidative phosphorylation by mitochondrial complex I inhibitors suppressed HIV-1 infection in Jurkat cells, while forcing expression of genes involved in ETC rescued the deficiency of HIV-1 replication in NLRX1-deficient cells. Importantly, treating humanized mice with FDA-approved drug, metformin which targets mitochondrial complex I, significantly reduced HIV-1 viral load. This study demonstrated the potential of targeting NLRX1 and applying metformin in suppressing HIV-1 replication in patients.