Summary Current therapeutic interventions to eradicate latent HIV (“reservoir”) and restore immune function in ART-treated HIV infection have yet to show efficacy. To explore mechanisms of HIV persistence, we apply an integrated systems biology approach and identify a distinct group of individuals with poor CD4 T-cell reconstitution (Immunologic non-responders, “INRs”) and high frequencies of cells with inducible HIV. Contrary to the prevailing notion that immune activation drives HIV persistence and immune dysfunction, peripheral blood leukocytes from these subjects have enhanced expression of a network of genes regulated by cellular senescence driving transcription factors (TFs) FOXO3, SMAD2 and IRF3. In these subjects, increased frequencies of regulatory T cells and expression of the TGF-β signaling cascade are complimented by the downregulation of cell cycle, metabolic and pro-inflammatory pathways. Lactobacillaceae family and metabolites (members of the butyrate family – i.e. α-ketobutyrate) were correlated with Treg frequencies in “Senescent-INRs” ex vivo, triggered the differentiation of TGF-β producing Tregs and promoted HIV latency establishment in vitro. These cascades, downstream of PD-1/TGF-β, prevent memory T cell differentiation and are associated with an increase in frequencies of cells with inducible HIV ex vivo. Our findings identify cellular senescence responses that can be targeted by PD-1 or TGF-β specific interventions that have shown safety and efficacy in cancer, and may prove to be crucial for HIV eradication.

Microbiome and Metabolome driven differentiation of TGF-β producing Tregs leads to Senescence and HIV latency