Defensins in STI-mediated enhancement of HIV Infection

描述(申请人提供)：性传播是最常见的艾滋病毒感染途径。妇女占全世界感染者的近一半，在撒哈拉以南非洲占70%以上(联合国艾滋病规划署2006年报告)。需要采取不同方法的预防战略，以减少传播的可能性。流行病学和临床研究有力地表明，性传播感染增加了艾滋病毒传播的可能性。尽管性传播感染对艾滋病毒传播增加的贡献可能是多方面的，但了解性传播感染如何增强艾滋病毒感染对于制定减少艾滋病毒传播的新战略至关重要。 哺乳动物防御素是重要的天然宿主防御抗菌肽，被认为在粘膜免疫中发挥作用。人类防御素5和6(HD5和HD6)在肠道Paneth细胞中有结构性表达，在阴道和宫颈外上皮中有HD5的表达。最近在沙眼衣原体和淋球菌感染的男性尿路中发现了HD5的诱导，这支持了在性传播感染中的作用。然而，在我们的初步研究中出现了一个更复杂的情况，表明HD5和HD6在病毒进入阶段显著增加了艾滋病毒的感染。利用宫颈阴道组织培养系统，我们首次发现，淋球菌感染诱导了HD5和HD6。因此，我们推测性传播感染可能是由于生殖器粘膜中HD5和HD6的高水平诱导而导致这些个体中艾滋病毒传播的增加。 这项建议的目的是开始剖析HD5和HD6介导的促进HIV-1进入的机制，并探索它们在利用我们的新的体外感染系统促进性传播感染方面的假定作用。机制研究将确定HD5增强病毒感染的具体步骤，HD6将定义增强是否通过对病毒和/或靶细胞的直接影响，并将开始确定病毒gp120的可能对此增强至关重要的成分。这项研究将进一步深入了解防御素在HIV-1致病和传播中的复杂功能，并研究这种宿主反应与候选局部杀微生物剂之间的相互作用。更长期的结果可能是制定新的预防战略。

DESCRIPTION (provided by applicant): Sexual transmission is the most common route of HIV infection. Women account for nearly half of those infected worldwide and more than 70% in sub-Saharan Africa (UNAIDS report 2006). 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 to reduce the spread of HIV. Mammalian defensins are antimicrobial peptides important to innate host defense and are thought to play a role in mucosal immunity. Human defensins 5 and 6 (HD5 and HD6) are constitutively expressed in intestinal Paneth cells and HD5 is found in the epithelium of the vagina and ectocervix. Induction of HD5 has been recently found in the male urethra during C. trachomatis and N. gonorrhoeae infection, supporting a role in STIs. However, a more complex picture emerged in our preliminary studies indicating that HD5 and HD6 significantly enhance HIV infection at the step of viral entry. Using cervicovaginal tissue culture systems, we found that, for the first time, HD5 and HD6 were induced in response to gonococcal infection. Therefore, we hypothesize STIs may contribute to increased HIV transmission in these individuals due the high level induction of HD5 and HD6 in the genital mucosa. The goal of this proposal is to begin to dissect the mechanism of HD5 and HD6-mediated enhancement of HIV-1 entry and to explore their putative role in facilitating transmission in conjunction with STIs employing our novel in vitro infection system. Mechanistic studies will define the specific step in viral infection that is enhanced by HD5 and HD6 will define if the enhancement is through direct effects on the virus and/or the target cell and will start to define components of viral gp120 that might be critical to this enhancement. This study will provide further insight into the complex function of defensins in HIV-1 pathogenesis and transmission, and investigate the interaction between this host response and candidate topical microbicides. A longer term outcome could be the development of novel prevention strategies.