Immunologic Uniqueness of the Female Genital Tract in HIV Pathogenesis

描述（由申请方提供）：对过去十年中积累的流行病学、病毒学和免疫学数据进行了严格评价，得出的必然结论是，HIV-1感染必须主要被视为一种粘膜疾病。绝大多数HIV-1感染是在阴道和肛门性交时通过粘膜途径感染的，妇女感染的频率高于男子。一些潜在的机制，解决实验在这个建议中，可能涉及在跨粘膜的免费和细胞相关的HIV的传输。穿透HIV-1迅速感染上皮下靶细胞（主要是CD 4 + T细胞），导致粘膜组织中的这种细胞群显著广泛耗竭，特别是在肠道和其他粘膜器官和组织中，包括女性生殖道。据推测，由于粘膜T细胞耗竭和免疫调节机制的破坏，粘膜防御严重受损，环境抗原，主要是细菌来源的，以高得多的速率被吸收，并激活驻留在全身免疫区室中的靶细胞。此外，在人类中进行的许多研究强烈表明，使用基于炔雌醇的体液避孕药与HIV-1感染风险显著增加之间存在显著关联。提交的提案代表了一种综合方法，重点是粘膜免疫系统的一个独特部分-女性生殖道-和HIV-1感染。根据本申请的各个组成部分，整个提案的总体具体目标将涉及：1）HIV-1进入和感染女性生殖道的免疫生物学，涉及HIV-1进入和HIV-1感染易感性相关细胞及其受体的鉴定，以及抗体在预防HIV-1感染中的作用; 2）女性生殖道中体液应答的显著改变，即感染女性中HIV-1特异性伊加应答的意外缺乏，以及HIV-1诱导的T和B细胞中粘膜和全身淋巴细胞归巢受体表达的变化;和3）基于炔雌醇的避孕药对HIV-1感染妇女粘膜免疫的影响。如本提案核心B部分所述，这些研究的成功取决于能否获得适当的妇女群体。

DESCRIPTION (provided by applicant): Critical evaluation of epidemiological, virological, and immunological data accumulated during the last decade leads to the inevitable conclusion that HIV-1 infection must be considered primarily as a mucosal disease. The absolute majority of HIV-1 infections are encountered by the mucosal route during vaginal and anal sexual encounters, with women infected at a higher frequency than males. A number of potential mechanisms, addressed experimentally in this proposal, may be involved in the transmission of free and cell associated HIV across mucosal membranes. Penetrating HIV-1 promptly infects subepithelial target cells (mostly CD4+ T cells), resulting in a remarkably extensive depletion of this cell population in mucosal tissues, particularly in the gut and other mucosal organs and tissues including the female genital tract. It is speculated that as a consequence of mucosal T cell depletion and the resulting breakdown of immunoregulatory mechanisms, mucosal defenses are severely impaired and environmental antigens, mainly of bacterial origin, are taken up at much higher rates and activate target cells residing in the systemic immune compartment. Furthermore, numerous studies performed in humans strongly suggest that there is a significant association between the use of progesterone-based humoral contraceptives and a markedly increased risk of HIV-1 infection. The submitted proposal represents an integrated approach focused on a unique compartment of the mucosal immune system - the female genital tract - and HIV-1 infection. Based on the individual components of this application, the overall specific aims of the entire proposal will address: 1) the immunobiology of HIV-1 entry and infection in the female genital tract with respect to the identification of cells and their receptors involved in HIV-1 entry and susceptibility to HIV-1 infection, and the role of antibodies in the prevention of HIV-1 infection; 2) marked alterations of humoral responses in the female genital tract with respect to the unexpected paucity of HIV-1-specific IgA responses in infected women, and HIV-1-induced changes in T and B cells with respect to the expression of mucosal and systemic lymphocyte homing receptors; and 3) the impact of progesterone-based contraceptives on mucosal immunity in HIV-1- infected women. The success of these studies is dependent on accessibility to suitable cohorts of women, as specified and described in the Core B section of this proposal.