title: The transcriptome of HIV-1 infected intestinal CD4+ T cells exposed to enteric bacteria.
abstract: Global transcriptome studies can help pinpoint key cellular pathways exploited by viruses to replicate and cause pathogenesis. Previous data showed that laboratory-adapted HIV-1 triggers significant gene expression changes in CD4+ T cell lines and mitogen-activated CD4+ T cells from peripheral blood. However, HIV-1 primarily targets mucosal compartments during acute infection in vivo. Moreover, early HIV-1 infection causes extensive depletion of CD4+ T cells in the gastrointestinal tract that herald persistent inflammation due to the translocation of enteric microbes to the systemic circulation. Here, we profiled the transcriptome of primary intestinal CD4+ T cells infected ex vivo with transmitted/founder (TF) HIV-1. Infections were performed in the presence or absence of Prevotella stercorea, a gut microbe enriched in the mucosa of HIV-1-infected individuals that enhanced both TF HIV-1 replication and CD4+ T cell death ex vivo. In the absence of bacteria, HIV-1 triggered a cellular shutdown response involving the downregulation of HIV-1 reactome genes, while perturbing genes linked to OX40, PPAR and FOXO3 signaling. However, in the presence of bacteria, HIV-1 did not perturb these gene sets or pathways. Instead, HIV-1 enhanced granzyme expression and Th17 cell function, inhibited G1/S cell cycle checkpoint genes and triggered downstream cell death pathways in microbe-exposed gut CD4+ T cells. To gain insights on these differential effects, we profiled the gene expression landscape of HIV-1-uninfected gut CD4+ T cells exposed to bacteria. Microbial exposure upregulated genes involved in cellular proliferation, MAPK activation, Th17 cell differentiation and type I interferon signaling. Our findings reveal that microbial exposure influenced how HIV-1 altered the gut CD4+ T cell transcriptome, with potential consequences for HIV-1 susceptibility, cell survival and inflammation. The HIV-1- and microbe-altered pathways unraveled here may serve as a molecular blueprint to gain basic insights in mucosal HIV-1 pathogenesis.
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States of America.
authors.forename: Alyson C
authors.identifier: 0000-0003-1939-5527
authors.initials: AC
authors.lastname: Yoder
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States of America.|RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, United States of America.
authors.forename: Kejun
authors.identifier: 0000-0003-1121-7603
authors.initials: K
authors.lastname: Guo
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States of America.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Dillon
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States of America.|The Cancer Center, University of Colorado School of Medicine, Aurora, CO, United States of America.
authors.forename: Tzu
authors.initials: T
authors.lastname: Phang
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States of America.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States of America.|Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States of America.
authors.forename: Michael S
authors.identifier: 0000-0003-4182-2820
authors.initials: MS
authors.lastname: Harper
authors.affiliation: The Cancer Center, University of Colorado School of Medicine, Aurora, CO, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Helm
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.|Center for AIDS Research, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: John C
authors.initials: JC
authors.lastname: Kappes
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.|Center for AIDS Research, University of Alabama at Birmingham, Birmingham, AL, United States of America.
authors.forename: Christina
authors.identifier: 0000-0003-1166-5879
authors.initials: C
authors.lastname: Ochsenbauer
authors.affiliation: Department of Surgery, University of Colorado School of Medicine, Aurora, CO, United States of America.
authors.forename: Martin D
authors.initials: MD
authors.lastname: McCarter
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States of America.|RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, United States of America.|Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States of America.
authors.forename: Cara C
authors.identifier: 0000-0002-3955-2326
authors.initials: CC
authors.lastname: Wilson
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States of America.|RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, United States of America.|Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States of America.
authors.forename: Mario L
authors.identifier: 0000-0001-7792-2706
authors.initials: ML
authors.lastname: Santiago
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000382:microbiology*; D004755:Enterobacteriaceae; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000382:microbiology*; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D007422:Intestines / Q000382:microbiology*; D059467:Transcriptome