Microbiome And Metabolome Driven Differentiation Of TGF-β Producing Tregs Leads to Senescence and HIV Latency

Therapeutic interventions to eradicate latent HIV in ART-treated infection have yet to show efficacy. We used a systems biology approach to identify a subset of ART-treated individuals with immune-dysfunction that had the highest frequencies of cells with inducible HIV. Contrary to the prevailing notion that immune activation drives HIV persistence, blood from these individuals was enriched in senescence-inducing genes (high FOXO3, SMAD2 and IRF3), Treg frequencies and TGF-β signaling expression. In these "Senescent-INRs", high Firmicute phylum plasma nucleotides and butyrate/bile acids (like a-ketobutyrate) correlated with Treg frequencies and inducible HIV levels. Stimulation of naive CD4 T-cells with a-ketobutyrate led to TGF-β producing Treg differentiation, and PD-1 up-regulation on less differentiated cells. A dose dependent increase in latent HIV-infected memory CD4 T-cells was observed after TGF-β stimulation. Senescence cascades identified here can be targeted by PD-1/TGF-β specific interventions that have shown safety/efficacy in cancer, and can be crucial for HIV eradication.