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CD4 receptor diversity in chimpanzees protects against SIV infection.

ABSTRACT: Human and simian immunodeficiency viruses (HIV/SIVs) use CD4 as the primary receptor to enter target cells. Here, we show that the chimpanzee CD4 is highly polymorphic, with nine coding variants present in wild populations, and that this diversity interferes with SIV envelope (Env)-CD4 interactions. Testing the replication fitness of SIVcpz strains in CD4+ T cells from captive chimpanzees, we found that certain viruses were unable to infect cells from certain hosts. These differences were recapitulated in CD4 transfection assays, which revealed a strong association between CD4 genotypes and SIVcpz infection phenotypes. The most striking differences were observed for three substitutions (Q25R, Q40R, and P68T), with P68T generating a second N-linked glycosylation site (N66) in addition to an invariant N32 encoded by all chimpanzee CD4 alleles. In silico modeling and site-directed mutagenesis identified charged residues at the CD4-Env interface and clashes between CD4- and Env-encoded glycans as mechanisms of inhibition. CD4 polymorphisms also reduced Env-mediated cell entry of monkey SIVs, which was dependent on at least one D1 domain glycan. CD4 allele frequencies varied among wild chimpanzees, with high diversity in all but the western subspecies, which appeared to have undergone a selective sweep. One allele was associated with lower SIVcpz prevalence rates in the wild. These results indicate that substitutions in the D1 domain of the chimpanzee CD4 can prevent SIV cell entry. Although some SIVcpz strains have adapted to utilize these variants, CD4 diversity is maintained, protecting chimpanzees against infection with SIVcpz and other SIVs to which they are exposed.

SUBMITTER: Bibollet-Ruche F

PROVIDER: S-EPMC6386711 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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CD4 receptor diversity in chimpanzees protects against SIV infection.

Bibollet-Ruche Frederic F Russell Ronnie M RM Liu Weimin W Stewart-Jones Guillaume B E GBE Sherrill-Mix Scott S Li Yingying Y Learn Gerald H GH Smith Andrew G AG Gondim Marcos V P MVP Plenderleith Lindsey J LJ Decker Julie M JM Easlick Juliet L JL Wetzel Katherine S KS Collman Ronald G RG Ding Shilei S Finzi Andrés A Ayouba Ahidjo A Peeters Martine M Leendertz Fabian H FH van Schijndel Joost J Goedmakers Annemarie A Ton Els E Boesch Christophe C Kuehl Hjalmar H Arandjelovic Mimi M Dieguez Paula P Murai Mizuki M Colin Christelle C Koops Kathelijne K Speede Sheri S Gonder Mary K MK Muller Martin N MN Sanz Crickette M CM Morgan David B DB Atencia Rebecca R Cox Debby D Piel Alex K AK Stewart Fiona A FA Ndjango Jean-Bosco N JN Mjungu Deus D Lonsdorf Elizabeth V EV Pusey Anne E AE Kwong Peter D PD Sharp Paul M PM Shaw George M GM Hahn Beatrice H BH

Proceedings of the National Academy of Sciences of the United States of America 20190204 8

Human and simian immunodeficiency viruses (HIV/SIVs) use CD4 as the primary receptor to enter target cells. Here, we show that the chimpanzee CD4 is highly polymorphic, with nine coding variants present in wild populations, and that this diversity interferes with SIV envelope (Env)-CD4 interactions. Testing the replication fitness of SIVcpz strains in CD4<sup>+</sup> T cells from captive chimpanzees, we found that certain viruses were unable to infect cells from certain hosts. These differences ...[more]

PMID: 30718403

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Project description: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.IMPORTANCEHuman 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.

Dataset Information

CD4 receptor diversity in chimpanzees protects against SIV infection.

Publications

CD4 receptor diversity in chimpanzees protects against SIV infection.

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