Mycobacterium tuberculosis reactivates HIV via exosomes mediated resetting of cellular redox potential and bioenergetics

The synergy between () and HIV-1 interferes with therapy and facilitates pathogenesis of both human pathogens. Fundamental mechanisms by which exacerbates HIV-1 are not clear. Here, we show that exosomes secreted by macrophages infected with , including drug-resistant clinical strains, reactivate HIV-1 by inducing oxidative stress. Mechanistically, -specific exosomes realign mitochondrial and non-mitochondrial oxygen consumption rate (OCR) and modulates the expression of genes mediating oxidative stress response, inflammation, and HIV-1 transactivation. Proteomics revealed the enrichment of several host factors ( HIF-1α, galectins, Hsp90) known to promote HIV-1 reactivation in the -specific exosomes. Treatment with a known antioxidant, N-acetyl cysteine, or with the inhibitors of host factors galectins and Hsp90 attenuated HIV-1 reactivation by -specific exosomes. Our findings uncovered new paradigms for understanding the redox and bioenergetics basis of HIV-TB co-infection, which will enable the design of effective therapeutic strategies.