TGF-β Signaling, Senescence and Impaired Metabolism in Central Memory CD4 T Cells Promotes HIV Persistence

Therapeutic interventions to eradicate latent HIV and restore immune function in ART-treated infection have yet to show efficacy. We applied an integrated -omic approach to identify a distinct group of individuals with poor CD4 T-cell reconstitution (Senescent Immunologic non-responders, “Senescent-INRs”) and the highest frequencies of CD4 T cells with inducible HIV. Contrary to the notion that immune activation drives HIV persistence and immune dysfunction, leukocytes of these subjects expressed genes that regulate cellular senescence. Here, increased frequencies of Tregs and TGF-β signaling cascade expression coincided with downregulation of cell metabolism/cycling in PD1-expressing central memory CD4 T cells and with frequencies of cells with inducible HIV. This profile, driven by a β-hydroxybutyrate rich metabolic milieu, resulted in TGF-β associated latency establishment/maintenance. Our findings identify cellular senescence as a novel mechanism of HIV persistence, that can be targeted by PD-1 or TGF-β specific interventions that have shown safety and efficacy in cancer.