Defensins in STI-Mediated Enhanced HIV Infectivity

项目摘要 性传播是艾滋病毒感染的最常见途径，妇女占近一半。 感染者遍布全球。需要采取不同的预防战略， 传播的可能性。流行病学和临床研究强烈表明，性传播疾病 性传播感染（STI）增加了艾滋病毒传播的可能性。虽然科技机构对增长的贡献 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于 制定预防艾滋病毒的新战略。 哺乳动物防御素是一种对宿主先天防御非常重要的抗菌肽， 粘膜免疫人防御素5和6（HD 5和HD 6），在哺乳动物中最丰富的抗微生物肽， 肠，组成型表达于潘氏细胞，但也见于阴道上皮， 子宫颈在C. trachomatis和N.淋病 感染，进一步支持防御素在粘膜免疫中对STI的作用。然而，我们最近 该出版物表明，HD 5和HD 6在病毒进入步骤中显著增强HIV感染。使用 宫颈阴道上皮组织培养系统，我们证明，第一次，诱导HD 5和 HD 6对淋球菌（GC）感染的反应增加了HIV的感染性。HD 5的HIV增强作用和 与X4病毒相比，HD 6与R5病毒更明显，表明其与R5病毒一样具有临床意义 几乎都是通过性传播检测到的。我们假设性传播感染可能导致 通过上调先天效应物增加HIV传播，进而促进生殖器中的HIV感染性 粘膜防御素介导的HIV感染性增强的结果可能导致HIV感染性降低。 潜在杀微生物剂和中和抗体的效力。 这项建议的目的是剖析防御素介导的增强艾滋病毒感染性的分子基础 并评估宫颈阴道上皮细胞中HD 5和HD 6的转录调节对GC的响应 感染我们将确定HIV糖蛋白gp 120在防御素介导的HIV增强中的作用。 传染性我们将研究HD 5和HD 6增强HIV作用的分子决定因素。我们 将阐明GC感染对HD 5和HD 6基因调控的潜在机制。本研究将 为更好地理解防御素在HIV-1发病机制和粘膜中的复杂功能提供了一个新的视角。 传播，并提供深入了解新的预防战略的发展，特别是在 性病

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.