Immunometabolic reprogramming by caloric restriction leads to protection from SIV in rhesus macaques 3052

Description Nutrient metabolism influences HIV-1 replication, immunity, and chronic inflammation, yet it is challenging to target therapeutically. We hypothesized that modulating metabolism via caloric restriction (CR), a safe, anti-aging modality with anti-inflammatory effects could improve SIV disease outcome in rhesus macaques (RMs). Healthy, non-obese, Indian RMs (n = 6) were restricted to 30% fewer daily calories than their ad-libitum (AL) intake. After 3 months of CR, they were infected with SIVmac239, left untreated for 28 days, and then given ART for 11 months while maintaining CR. They were compared to age-, gender-, and weight-matched AL-fed RMs (n = 11). CR led to an approximately 1 log reduction in acute-phase viremia compared to the AL cohort, along with significantly greater memory CD8 T cell proliferative response at prominent tissue sites of SIV replication. Plasma metabolomics showed that CR induced a predominant glycolytic signature and 3 metabolites: spermidine, glucose-6-phosphate, and ADP strongly predicted lower plasma SIV AUC. Ex vivo glycolytic flux and mTORC1 activity were also higher in PBMCs and memory CD8 T cells at acute SIV, respectively. 11 months post-ART, CR cohort exhibited reduced levels of HLA-DR+ CD4 and CD8 memory T cells in the colon and lower plasma levels of the gut permeability marker sCD14. Improved gut health in CR was associated with elevated TCA-cycle intermediates. Thus, the data shows that CR has a profoundly positive impact on SIV pathogenesis. Funding Sources NIH R01 AI67644-01A1; NIH R21 AI74901-01; NIH R21 OD031229.