Defensins in STI-Mediated Enhanced HIV Infectivity

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DESCRIPTION (provided by applicant): Sexual transmission is the most common route of HIV infection and women account for nearly half of those infected worldwide. Prevention strategies employing different approaches are needed to reduce the probability of transmission. Epidemiologic and clinical studies strongly indicate that sexually transmitted infections (STIs) increase the likelihood of HIV transmission. Although the contribution of STIs to the increase in HIV transmission is likely to be multifaceted (38, 84), understanding how STIs enhance HIV infection is vital to the development of new strategies for the prevention of HIV. Defensins are antimicrobial peptides important to innate mucosal immunity. Indeed, the levels of defensins in genital fluid are frequently elevated in individuals with STIs, suggesting a potential role in modulating HIV transmission. Human defensins 5 and 6 (HD5 and HD6) are the most abundant antimicrobial peptides in the intestine, a major site of CD4+ T cell depletion during acute HIV infection. HD5 and HD6 are constitutively expressed in Paneth cells, but also found in the female genital mucosa. Induction of HD5 has been reported in genital fluid from individuals with C. trachomatis (CT) and N. gonorrhoeae (GC) infection, and bacterial vaginosis (BV). Our recent publication indicates that HD5 and HD6 significantly enhance HIV infectivity and that induction of these defensins contributes to enhanced HIV infection of conditioned media from N. gonorrhoeae-exposed vaginal epithelial cells. The HIV enhancing effect of HD5 and HD6 is more pronounced with R5 virus compared to X4 virus, suggesting its clinical significance as R5 viruses are almost exclusively detected upon sexual transmission. Importantly, we obtained and analyzed endocervical specimens from women with or without CT infection and found that HD5 proteins were elevated in clinical specimens from CT-infected women. Additionally, elevated levels of HD5 in endocervical specimens from women with STIs were associated with enhanced in vitro HIV infectivity. We hypothesize that STIs may contribute to increased HIV transmission by up-regulating innate effectors such as defensins that in turn promote HIV infectivity and induce inflammatory responses in the genital mucosa. The consequence of elevated levels of defensins in response to STIs may not only lead to increased susceptibility to HIV infection but also negatively impact the efficacy of microbicides and antibody-inducing vaccines. The goal of this proposal is to establish the role of defensins in STI-mediated enhanced HIV infectivity and dissect its underlying molecular mechanism. This study will provide a better understanding of the complex function of defensins in mucosal transmission of HIV, and offer insight into the development of novel prevention strategies, especially in the setting of STIs. PUBLIC HEALTH RELEVANCE: The goal of this project is aim to understand the role of defensins in sexual transmitted infection (STI)-mediated enhancement of HIV infectivity.