title: Enhanced human immunodeficiency virus Type 1 expression and neuropathogenesis in knockout mice lacking Type I interferon responses.
abstract: The roles of Type I interferon (IFN) in human immunodeficiency virus Type 1 (HIV-1) neuropathogenesis are poorly understood; both protective and deleterious effects of IFN signaling have been described. We used genetically modified mice deficient in the Type I IFN receptor (IFNRKO) to analyze the progress of HIV-1 brain infection and neuropathogenesis in the absence of IFN signaling. IFNRKO and wild-type (WT) mice on the 129xSv/Ev or C57BL/6 strain backgrounds were infected systemically with EcoHIV, a chimeric HIV-1 that productively infects mice. IFNRKO mice showed higher HIV-1 expression in spleen and peritoneal macrophages and greater virus infiltration into the brain compared to WT mice. Neuropathogenesis was studied by histopathological, immunohistochemical, immunofluorescence, and polymerase chain reaction analyses of brain tissues after the virus was inoculated into the brain by stereotaxic intracerebral injection. Both IFNRKO and WT mice showed readily detectable HIV-1 and brain lesions, including microglial activation, astrocytosis, and increased expression of genes coding for inflammatory cytokines and chemokines typical of human HIV-1 brain disease. Parameters of HIV-1 neuropathogenesis, including HIV-1 expression in microglia/macrophages, were significantly greater in IFNRKO than in WT mice. Our results show unequivocally that Type I IFN signaling and responses limit HIV-1 infection and pathogenesis in the brains of mice.
authors: From the Molecular Virology Division, St. Luke's-Roosevelt Hospital Center, and Department of Pathology & Cell Biology (HH, WC, C-JG, AB, EH, JK, KI, MJP, DJV), Columbia University, New York, New York; Department of Pathology and Laboratory Medicine (LRS, MD), Rutgers New Jersey Medical School, Newark, New Jersey.
authors: Hongxia
authors: H
authors: He
authors: Leroy R
authors: LR
authors: Sharer
authors: Wei
authors: W
authors: Chao
authors: Chao-Jiang
authors: CJ
authors: Gu
authors: Alejandra
authors: A
authors: Borjabad
authors: Eran
authors: E
authors: Hadas
authors: Jennifer
authors: J
authors: Kelschenbach
authors: Koji
authors: K
authors: Ichiyama
authors: Meilan
authors: M
authors: Do
authors: Mary Jane
authors: MJ
authors: Potash
authors: David J
authors: DJ
authors: Volsky
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D007370:Interferon Type I / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D007370:Interferon Type I