Epigenetic control of IRF1 responses in HIV-exposed seronegative versus HIV-susceptible individuals

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 immun...

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Bibliographic Details
Published in:Blood 2011-03, Vol.117 (9), p.2649-2657
Main Authors: Su, Ruey-Chyi, Sivro, Aida, Kimani, Joshua, Jaoko, Walter, Plummer, Francis A., Ball, T. Blake
Format: Article
Language:English
Subjects:
Acetylation - drug effects
Biological and medical sciences
Case-Control Studies
Data processing
Disease Susceptibility
Down-Regulation - drug effects
Epigenesis, Genetic - drug effects
Gene Silencing - drug effects
Genetic Loci
Hematologic and hematopoietic diseases
Histone Deacetylase 2 - metabolism
Histones - metabolism
HIV Infections - genetics
HIV Infections - immunology
HIV Seronegativity - genetics
Human immunodeficiency virus 1
Human viral diseases
Humans
Immunobiology
Infectious diseases
Interferon Regulatory Factor-1 - genetics
Interferon Regulatory Factor-1 - metabolism
Interferon-gamma - pharmacology
Kinetics
Medical sciences
NF-kappa B - metabolism
Promoter Regions, Genetic - genetics
Protein Binding - drug effects
RNA, Messenger - genetics
RNA, Messenger - metabolism
STAT1 Transcription Factor - metabolism
Transcription Factor RelA - metabolism
Viral diseases
Viral diseases of the lymphoid tissue and the blood. Aids
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Summary: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.
ISSN:0006-4971
1528-0020
1528-0020
DOI:10.1182/blood-2010-10-312462