Reduced plasma retinoids during SIV are associated with bile acid dysregulation, tryptophan metabolism, and markers of disease progression

Summary: Introduction: Despite effective antiretroviral therapies (ART), people with HIV (PWH) remain at elevated risk of HIV-associated co-morbidities, which are thought to result from persistent chronic immune activation and inflammation. These immune dysregulations have been associated with gut barrier damage that also persists, even during ART. HIV is associated with dysregulation of metabolic pathways associated with tryptophan catabolism and retinoic acid signaling. However, the relationship between these disturbances, gut damage, and HIV-associated co-morbidities remains poorly understood. Methods: Eighteen pig-tailed macaques (PTMs; Macaca nemestrina) were infected with 300 TCID SIVsab, generating a nonhuman primate model of HIV disease progression. Six PTMs were administered ART (DTG+3TC+TDF) IV daily beginning day 48. Plasma metabolic profiling was performed by Metabolon. Complete blood counts, serum chemistry, and lymphocyte immunophenotyping with flow cytometry were performed longitudinally, including at pre-, acute, setpoint, and chronic infection. Statistical analyses included Wilcoxon tests and Pearson correlation. Results: In both groups, bile acid (BA) metabolism was the most dysregulated pathway. During acute infection, primary BAs cholate (P=0.002) and chenodeoxycholate (P=0.02) were significantly reduced, while glycine- and taurine-conjugated BAs were significantly increased. These changes were only partially ameliorated by ART. Importantly, glycine-conjugated BAs were negatively associated with pro-vitamin A (retinoic acid precursor) compounds (beta-cryptoxanthin, carotene diols (1), (2), and (3)), while taurine-conjugated BAs were negatively associated with retinol and retinal. Like cholate and chenodeoxycholate, retinoids were significantly decreased during acute infection and only partially restored by ART. Carotenoids beta-cryptoxanthin, carotene diols (1), and (3) were positively associated with tryptophan (r=0.495, P<0.0001; r=0.418, P=0.0001; r=0.417, P=0.0001; respectively) and negatively with its metabolite kynurenine (r=-0.368, P=0.0009; r=-0.308, P=0.006; r=-0.295, P=0.008). Kynurenine was increased during acute infection (P=0.002) and partially reduced by ART (P=0.312) but remained elevated compared to pre-infection (P=0.0312). Kynurenine was further associated with markers of disease progression including lymphocyte dysregulation (CD4 counts: r=-0.605, P<0.0001; CD38+HLA-DR+CD4+ cells: r=0.313, P=0.005; Ki67+CD8+ cells: r=0.491, P<0.0001) myeloid cell activation (sCD163: r=0.566, P<0.0001; neopterin: r=0.514, P<0.0001), liver damage (AST: r=0.546, P=0.001, ALT: r=0.479, P=0.006), and hypercoagulability (D dimer: r=0.587, P<0.0001; platelets: r=-0.548, P<0.0001). Conclusion: BAs are significantly dysregulated during inflammatory bowel diseases (IBDs) and are required for absorption of lipophilic nutrients like vitamin A. Their loss may provide an explanation for decreased systemic retinoid levels during HIV and IBDs, and the correlation of retinoids with kynurenine provides a novel and potentially targetable contributor to disease progression. Although suggestive, further studies are required to elucidate these interactions during HIV/SIV. Cuiling Xu, Kevin D. Raehtz, Cristian Apetrei, and Ivona Pandrea