Lipid metabolic reprogramming of hepatic CD4 + T cells during SIV infection

Abstract

ABSTRACT While liver inflammation is associated with AIDS, little is known so far about hepatic CD4 + T cells. By using the simian immunodeficiency virus (SIV)-infected rhesus macaque (RM) model, we aimed to characterize CD4 + T cells. The phenotype of CD4 + T cells was assessed by flow cytometry from uninfected ( n = 3) and infected RMs, with either SIVmac251 ( n = 6) or SHIVSF162p3 ( n = 6). After cell sorting of hepatic CD4 + T cells, viral DNA quantification and RNA sequencing were performed.Thus, we demonstrated that liver CD4 + T cells strongly expressed the SIV coreceptor, CCR5. We showed that viremia was negatively correlated with the percentage of hepatic effector memory CD4 + T cells. Consistent with viral sensing, inflammatory and interferon gene transcripts were increased. We also highlighted the presence of harmful CD4 + T cells expressing GZMA and members of TGFB that could contribute to fuel inflammation and fibrosis. Whereas RNA sequencing demonstrated activated CD4 + T cells displaying higher levels of mitoribosome and membrane lipid synthesis transcripts, few genes were related to glycolysis and oxidative phosphorylation, which are essential to sustain activated T cells. Furthermore, we observed lower levels of mitochondrial DNA and higher levels of genes associated with damaged organelles (reticulophagy and mitophagy). Altogether, our data revealed that activated hepatic CD4 + T cells are reprogrammed to lipid metabolism. Thus, strategies aiming to reprogram T cell metabolism with effector function could be of interest for controlling viral infection and preventing liver disorders. IMPORTANCE Human immunodeficiency virus (HIV) infection may cause liver diseases, associated with inflammation and tissue injury, contributing to comorbidity in people living with HIV. Paradoxically, the contribution of hepatic CD4 + T cells remains largely underestimated. Herein, we used the model of simian immunodeficiency virus (SIV)-infected rhesus macaques to access liver tissue. Our work demonstrates that hepatic CD4 + T cells express CCR5, the main viral coreceptor, and are infected. Viral infection is associated with the presence of inflamed and activated hepatic CD4 + T cells expressing cytotoxic molecules. Furthermore, hepatic CD4 + T cells are reprogrammed toward lipid metabolism after SIV infection. Altogether, our findings shed new light on hepatic CD4 + T cell profile that could contribute to liver injury following viral infection.