title: The recombinant vaccinia virus gene product, B18R, neutralizes interferon alpha and alleviates histopathological complications in an HIV encephalitis mouse model.
abstract: Interferon-alpha (IFN-α) has been identified as a neurotoxin that plays a prominent role in human immunodeficiency virus (HIV)-associated neurocognitive disorders and HIV encephalitis (HIVE) pathology. IFN-α is associated with cognitive dysfunction in other inflammatory diseases where IFN-α is upregulated. Trials of monoclonal anti-IFN-α antibodies have been generally disappointing possibly due to high specificity to limited IFN-α subtypes and low affinity. We investigated a novel IFN-α inhibitor, B18R, in an HIVE/severe combined immunodeficiency (SCID) mouse model. Immunostaining for B18R in systemically treated HIVE/SCID mice suggested the ability of B18R to cross the blood-brain barrier (BBB). Real-time PCR indicated that B18R treatment resulted in a decrease in gene expression associated with IFN-α signaling in the brain. Mice treated with B18R were found to have decreased mouse mononuclear phagocytes and significant retention of neuronal arborization compared to untreated HIVE/SCID mice. Increased mononuclear phagocytes and decreased neuronal arborization are key features of HIVE. These results suggest that B18R crosses the BBB, blocks IFN-α signaling, and it prevents key features of HIVE pathology. These data suggest that the high affinity and broad IFN-α subtype specificity of B18R make it a viable alternative to monoclonal antibodies for the inhibition of IFN-α in the immune-suppressed environment.
authors.affiliation: 1 Department of Neurology, Emory University School of Medicine , Atlanta, Georgia .
authors.forename: Cari
authors.initials: C
authors.lastname: Fritz-French
authors.forename: Ramzi
authors.initials: R
authors.lastname: Shawahna
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Ward
authors.forename: Leonard E
authors.initials: LE
authors.lastname: Maroun
authors.forename: William R
authors.initials: WR
authors.lastname: Tyor
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy / Q000209:etiology; D005786:Gene Expression Regulation / Q000187:drug effects; D015658:HIV Infections / Q000150:complications / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D014616:Vaccinia virus / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D016898:Interferon-alpha; D011994:Recombinant Proteins; D014764:Viral Proteins; C067853:B18R protein, Vaccinia virus