HIV-susceptible individuals

Not all individuals exposed to HIV be-come infected. Understanding why these HIV-exposed seronegative individuals remain uninfected will help inform the development of preventative measures against HIV infection. Interferon regula-tory 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 commer-cial sex workers who can be epidemio-logically 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- stimulation, HIV-R individu-als demonstrated a robust, but transient response. We also found that the IRF1 promoter in HIV-R was primed by in-creased basal histone deacetylase-2 binding, independently of transcription regulators, STAT1 and nuclear factor-B/p65, implicating an epigenetic silenc-ing mechanism. Interestingly, the transi-tory IRF1 response in HIV-R was suffi-cient in comparable regulation of interleukin-12 and interleukin-4 expres-sion compared with the HIV-susceptible controls. This is the first study charac-terizing IRF1 responsiveness in individu-als who demonstrate altered susceptibil-ity to HIV infection. These data suggest that transitory IRF1 responsiveness in HIV-R may be one of the key contribu-tors to the altered susceptibility to HIV infection during the early stages of pri-mary HIV infection. (Blood. 2011;117(9): 2649-2657