Enhanced human immunodeficiency virus type 1 expression and neuropathogenesis in knockout mice lacking type i interferon responses

Hongxia He, Leroy R. Sharer, Wei Chao, Chao Jiang Gu, Alejandra Borjabad, Eran Hadas, Jennifer Kelschenbach, Koji Ichiyama, Meilan Do, Mary Jane Potash, David J. Volsky

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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.

Original languageEnglish
Pages (from-to)59-71
Number of pages13
JournalJournal of Neuropathology and Experimental Neurology
Volume73
Issue number1
DOIs
StatePublished - Jan 2014
Externally publishedYes

Keywords

  • HIV-1
  • IFN signaling
  • Interferon /A receptor
  • Neuropathogenesis
  • Receptor knockout mice
  • Stereotaxic injection
  • Type I interferon.

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