Defensins in STI-Mediated Enhanced HIV Infectivity

项目总结 性传播是最常见的艾滋病毒感染途径，女性占近一半 世界各地被感染的人。需要采用不同方法的预防策略来减少 传播概率。流行病学和临床研究强烈表明，性传播 感染(性传播感染)增加了艾滋病毒传播的可能性。尽管性传播感染对人口增长的贡献 在艾滋病毒的传播可能是多方面的，了解性传播感染如何增强艾滋病毒感染对 制定预防艾滋病毒的新战略。 哺乳动物防御素是一种抗菌肽，对天然宿主防御很重要，并在 粘膜免疫。人类防御素5和6(HD5和HD6)，是人类体内含量最丰富的抗菌肽 肠道，在Paneth细胞中有成分表达，但也在阴道和 宫颈外膜。据报道，沙眼衣原体和淋病奈瑟菌在男性尿路中诱导了HD5。 感染，进一步支持防御素在防御性传播感染的粘膜免疫中的作用。然而，我们最近 研究表明，在病毒进入阶段，HD5和HD6显著增加了HIV的感染。使用 在宫颈阴道上皮组织培养体系中，我们首次证明了HD5和HD5的诱导 HD6对淋球菌(GC)感染的反应增加了艾滋病毒的传染性。HD5和HD5对HIV的增强作用 与X4病毒相比，HD6与R5病毒的相关性更强，提示其作为R5病毒具有临床意义 几乎只在性传播时被检测到。我们假设性传播感染可能导致 通过上调先天效应因子增加艾滋病毒的传播，进而促进生殖器中的艾滋病毒感染性 粘膜。防御素介导的艾滋病毒感染性增强的结果可能导致 潜在杀微生物剂和中和抗体的效力。 这项提议的目的是剖析防御素介导的增强艾滋病毒传染性的分子基础。 并评估宫颈阴道上皮细胞中HD5和HD6的转录调控对GC的反应 感染。我们将确定HIV糖蛋白gp120在防御素介导的HIV增强中的作用 传染性。我们将研究HD5和HD6增强HIV作用的分子决定因素。我们 将阐明GC感染对HD5和HD6基因调控的机制。这项研究将 更好地了解防御素在HIV-1致病机理和粘膜中的复杂功能 传播和提供对制定新的预防战略的见解，特别是在 性传播疾病。

PROJECT SUMMARY 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.