title: Type I interferon upregulates Bak and contributes to T cell loss during human immunodeficiency virus (HIV) infection.
abstract: The role of Type I interferon (IFN) during pathogenic HIV and SIV infections remains unclear, with conflicting observations suggesting protective versus immunopathological effects. We therefore examined the effect of IFNα/β on T cell death and viremia in HIV infection. Ex vivo analysis of eight pro- and anti-apoptotic molecules in chronic HIV-1 infection revealed that pro-apoptotic Bak was increased in CD4+ T cells and correlated directly with sensitivity to CD95/Fas-mediated apoptosis and inversely with CD4+ T cell counts. Apoptosis sensitivity and Bak expression were primarily increased in effector memory T cells. Knockdown of Bak by RNA interference inhibited CD95/Fas-induced death of T cells from HIV-1-infected individuals. In HIV-1-infected patients, IFNα-stimulated gene expression correlated positively with ex vivo T cell Bak levels, CD95/Fas-mediated apoptosis and viremia and negatively with CD4+ T cell counts. In vitro IFNα/β stimulation enhanced Bak expression, CD95/Fas expression and CD95/Fas-mediated apoptosis in healthy donor T cells and induced death of HIV-specific CD8+ T cells from HIV-1-infected patients. HIV-1 in vitro sensitized T cells to CD95/Fas-induced apoptosis and this was Toll-like receptor (TLR)7/9- and Type I IFN-dependent. This sensitization by HIV-1 was due to an indirect effect on T cells, as it occurred in peripheral blood mononuclear cell cultures but not purified CD4+ T cells. Finally, peak IFNα levels and viral loads correlated negatively during acute SIV infection suggesting a potential antiviral effect, but positively during chronic SIV infection indicating that either the virus drives IFNα production or IFNα may facilitate loss of viral control. The above findings indicate stage-specific opposing effects of Type I IFNs during HIV-1 infection and suggest a novel mechanism by which these cytokines contribute to T cell depletion, dysregulation of cellular immunity and disease progression.
authors.affiliation: Department of Microbiology and Immunology, Center for Immunology and Vaccine Science, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Fraietta
authors.forename: Yvonne M
authors.initials: YM
authors.lastname: Mueller
authors.forename: Guibin
authors.initials: G
authors.lastname: Yang
authors.forename: Alina C
authors.initials: AC
authors.lastname: Boesteanu
authors.forename: Donald T
authors.initials: DT
authors.lastname: Gracias
authors.forename: Duc H
authors.initials: DH
authors.lastname: Do
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hope
authors.forename: Noshin
authors.initials: N
authors.lastname: Kathuria
authors.forename: Shannon E
authors.initials: SE
authors.lastname: McGettigan
authors.forename: Mark G
authors.initials: MG
authors.lastname: Lewis
authors.forename: Luis D
authors.initials: LD
authors.lastname: Giavedoni
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Jacobson
authors.forename: Peter D
authors.initials: PD
authors.lastname: Katsikis
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015497:HIV-1 / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular; D007223:Infant; D016898:Interferon-alpha / Q000276:immunology* / Q000378:metabolism; D016899:Interferon-beta / Q000276:immunology* / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D051199:Toll-Like Receptor 7 / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology*; D019562:Viral Load / Q000276:immunology; D014766:Viremia / Q000276:immunology / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000096:biosynthesis / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism
chemical_list: C494772:BAK1 protein, human; C491901:FAS protein, human; D016898:Interferon-alpha; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D050998:bcl-2 Homologous Antagonist-Killer Protein; D019014:fas Receptor; D016899:Interferon-beta