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. Epidemiological 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, understanding how STIs enhance HIV infection is vital to the development of new strategies for the prevention of HIV. Mammalian defensins are antimicrobial peptides important to innate host defense and play a role in mucosal immunity. Human defensins 5 and 6 (HD5 and HD6), the most abundant antimicrobial peptides in intestine, are constitutively expressed in Paneth cells but also found in the epithelium of the vagina and ectocervix. Induction of HD5 has been reported in the male urethra during C. trachomatis and N. gonorrhoeae infectioN, further supporting the role of defensins in the mucosal immunity against STIs. However, our recent publication indicates that HD5 and HD6 significantly enhance HIV infection at the step of viral entry. Using a cervicovaginal epithelial tissue culture system, we demonstrate that, for the first time, induction of HD5 and HD6 in response to gonococcal (GC) infection increases HIV infectivity. 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. We hypothesize that STIs may contribute to increased HIV transmission by up-regulation of innate effectors that in turn promote HIV infectivity in the genital mucosa. The consequence of defensin-mediated enhancement of HIV infectivity may result in reduction of efficacy of potential microbicides and neutralizing antibodies. The goal of this proposal is to dissect the molecular basis of defensin-mediated enhanced HIV infectivity and to assess transcriptional regulation of HD5 and HD6 in cervicovaginal epithelial cells in response to GC infection. We will define the role of HIV glycoprotein gp120 in defensin-mediated enhancement of HIV infectivity. We will investigate the molecular determinants for the HIV enhancing effect of HD5 and HD6. We will elucidate the mechanism underlying gene regulation of HD5 and HD6 by GC infection. This study will provide a better understanding of the complex function of defensins in HIV-1 pathogenesis and mucosal transmission and offer insight into the development of novel prevention strategies, especially in the setting of STIs.
|Tasker, Carley; Ding, Jian; Schmolke, Mirco et al. (2014) 17?-estradiol protects primary macrophages against HIV infection through induction of interferon-alpha. Viral Immunol 27:140-50|
|Aiyar, Ashok; Quayle, Alison J; Buckner, Lyndsey R et al. (2014) Influence of the tryptophan-indole-IFN? axis on human genital Chlamydia trachomatis infection: role of vaginal co-infections. Front Cell Infect Microbiol 4:72|
|Sperling, Rhoda; Kraus, Thomas A; Ding, Jian et al. (2013) Differential profiles of immune mediators and in vitro HIV infectivity between endocervical and vaginal secretions from women with Chlamydia trachomatis infection: a pilot study. J Reprod Immunol 99:80-7|
|Jarvis, Gary A; Chang, Theresa L (2012) Modulation of HIV transmission by Neisseria gonorrhoeae: molecular and immunological aspects. Curr HIV Res 10:211-7|
|Ding, Jian; Chang, Theresa L (2012) TLR2 activation enhances HIV nuclear import and infection through T cell activation-independent and -dependent pathways. J Immunol 188:992-1001|
|Rapista, Aprille; Ding, Jian; Benito, Bernadette et al. (2011) Human defensins 5 and 6 enhance HIV-1 infectivity through promoting HIV attachment. Retrovirology 8:45|
|Buckner, Lyndsey R; Schust, Danny J; Ding, Jian et al. (2011) Innate immune mediator profiles and their regulation in a novel polarized immortalized epithelial cell model derived from human endocervix. J Reprod Immunol 92:8-20|