title: Gut immune dysfunction through impaired innate pattern recognition receptor expression and gut microbiota dysbiosis in chronic SIV infection.
abstract: HIV targets the gut mucosa early in infection, causing immune and epithelial barrier dysfunction and disease progression. However, gut mucosal sensing and innate immune signaling through mucosal pattern recognition receptors (PRRs) during HIV infection and disease progression are not well defined. Using the simian immunodeficiency virus (SIV)-infected rhesus macaque model of AIDS, we found a robust increase in PRRs and inflammatory cytokine gene expression during the acute SIV infection in both peripheral blood and gut mucosa, coinciding with viral replication. PRR expression remained elevated in peripheral blood following the transition to chronic SIV infection. In contrast, massive dampening of PRR expression was detected in the gut mucosa, despite the presence of detectable viral loads. Exceptionally, expression of Toll-like receptor 4 (TLR4) and TLR8 was downmodulated and diverged from expression patterns for most other TLRs in the gut. Decreased mucosal PRR expression was associated with increased abundance of several pathogenic bacterial taxa, including Pasteurellaceae members, Aggregatibacter and Actinobacillus, and Mycoplasmataceae family. Early antiretroviral therapy led to viral suppression but only partial maintenance of gut PRRs and cytokine gene expression. In summary, SIV infection dampens mucosal innate immunity through PRR dysregulation and may promote immune activation, gut microbiota changes, and ineffective viral clearance.
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, California, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Glavan
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, California, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Gaulke
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, California, USA.
authors.forename: C
authors.initials: C
authors.lastname: Santos Rocha
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, California, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sankaran-Walters
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, California, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Hirao
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: Raffatellu
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, California, USA.
authors.forename: G
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, California, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Bäumler
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, California, USA.|Institute of Genetics and Biochemistry, Federal University of Uberlandia, Uberlandia, Brazil.
authors.forename: L R
authors.initials: LR
authors.lastname: Goulart
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, California, USA.|California National Primate Research Center, Davis, California, USA.
authors.forename: S
authors.initials: S
authors.lastname: Dandekar
mesh_terms: D000818:Animals; D002908:Chronic Disease; D064806:Dysbiosis / Q000276:immunology*; D000069196:Gastrointestinal Microbiome / Q000276:immunology*; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000276:immunology* / Q000382:microbiology; D006801:Humans; D057131:Immune Evasion; D018928:Immunity, Mucosal; D008253:Macaca mulatta; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D015398:Signal Transduction; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000382:microbiology; D015302:Simian Immunodeficiency Virus / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000235:genetics / Q000378:metabolism; D019562:Viral Load; D014779:Virus Replication
chemical_list: D051192:Receptors, Pattern Recognition; D051197:Toll-Like Receptor 4; D051200:Toll-Like Receptor 8