title: Epigenetic control of IRF1 responses in HIV-exposed seronegative versus HIV-susceptible individuals.
abstract: Not all individuals exposed to HIV become infected. Understanding why these HIV-exposed seronegative individuals remain uninfected will help inform the development of preventative measures against HIV infection. Interferon regulatory factor-1 (IRF1) plays a critical role both in host antiviral immunity and in HIV-1 replication. This study examined IRF1 expression regulation in the ex vivo peripheral blood mononuclear cells of HIV-exposed seronegative commercial sex workers who can be epidemiologically defined as relatively resistant to HIV infection (HIV-R), versus HIV-uninfected, susceptible controls (HIV-S). Whereas HIV-susceptible individuals demonstrated a biphasic, prolonged increase in IRF1 expression after interferon-γ stimulation, HIV-R individuals demonstrated a robust, but transient response. We also found that the IRF1 promoter in HIV-R was primed by increased basal histone deacetylase-2 binding, independently of transcription regulators, STAT1 and nuclear factor-κB/p65, implicating an epigenetic silencing mechanism. Interestingly, the transitory IRF1 response in HIV-R was sufficient in comparable regulation of interleukin-12 and interleukin-4 expression compared with the HIV-susceptible controls. This is the first study characterizing IRF1 responsiveness in individuals who demonstrate altered susceptibility to HIV infection. These data suggest that transitory IRF1 responsiveness in HIV-R may be one of the key contributors to the altered susceptibility to HIV infection during the early stages of primary HIV infection.
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada. su@cc.umanitoba.ca
authors.forename: Ruey-Chyi
authors.initials: RC
authors.lastname: Su
authors.forename: Aida
authors.initials: A
authors.lastname: Sivro
authors.forename: Joshua
authors.initials: J
authors.lastname: Kimani
authors.forename: Walter
authors.initials: W
authors.lastname: Jaoko
authors.forename: Francis A
authors.initials: FA
authors.lastname: Plummer
authors.forename: T Blake
authors.initials: TB
authors.lastname: Ball
mesh_terms: D000107:Acetylation / Q000187:drug effects; D016022:Case-Control Studies; D004198:Disease Susceptibility; D015536:Down-Regulation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D056426:Genetic Loci; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology; D018023:HIV Seronegativity / Q000235:genetics*; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007700:Kinetics; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D006657:Histones; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D016328:NF-kappa B; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D051996:Transcription Factor RelA; D007371:Interferon-gamma; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2