Sexual transmission is the most common route of HIV infection and women account for nearly half ofthose infected worldwide. Prevention strategies employing different approaches are needed to reduce theprobability of transmission. Epidemiological and clinical studies strongly indicate that sexually transmittedinfections (STIs) increase the likelihood of HIV transmission. Although the contribution of STIs to the increasein HIV transmission is likely to be multifaceted, understanding how STIs enhance HIV infection is vital to thedevelopment of new strategies for the prevention of HIV. Mammalian defensins are antimicrobial peptides important to innate host defense and play a role inmucosal immunity. Human defensins 5 and 6 (HD5 and HD6), the most abundant antimicrobial peptides inintestine, are constitutively expressed in Paneth cells but also found in the epithelium of the vagina andectocervix. Induction of HD5 has been reported in the male urethra during C. trachomatis and N. gonorrhoeaeinfectioN, further supporting the role of defensins in the mucosal immunity against STIs. However, our recentpublication indicates that HD5 and HD6 significantly enhance HIV infection at the step of viral entry. Using acervicovaginal epithelial tissue culture system, we demonstrate that, for the first time, induction of HD5 andHD6 in response to gonococcal (GC) infection increases HIV infectivity. The HIV enhancing effect of HD5 andHD6 is more pronounced with R5 virus compared to X4 virus, suggesting its clinical significance as R5 virusesare almost exclusively detected upon sexual transmission. We hypothesize that STIs may contribute toincreased HIV transmission by up-regulation of innate effectors that in turn promote HIV infectivity in the genitalmucosa. The consequence of defensin-mediated enhancement of HIV infectivity may result in reduction ofefficacy of potential microbicides and neutralizing antibodies. The goal of this proposal is to dissect the molecular basis of defensin-mediated enhanced HIV infectivityand to assess transcriptional regulation of HD5 and HD6 in cervicovaginal epithelial cells in response to GCinfection. We will define the role of HIV glycoprotein gp120 in defensin-mediated enhancement of HIVinfectivity. We will investigate the molecular determinants for the HIV enhancing effect of HD5 and HD6. Wewill elucidate the mechanism underlying gene regulation of HD5 and HD6 by GC infection. This study willprovide a better understanding of the complex function of defensins in HIV-1 pathogenesis and mucosaltransmission and offer insight into the development of novel prevention strategies, especially in the setting ofSTIs.
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