Immunologic Uniqueness of the Female Genital Tract in HIV Pathogenesis

女性生殖道在艾滋病毒发病机制中的免疫学独特性

• 批准号: 7936217
• 负责人: JIRI F MESTECKY
• 金额: $ 198.26万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-26 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936217
• 关键词: Immunologic; Uniqueness; Female; Genital; Tract

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.

描述（由申请人提供）：对过去十年中积累的流行病学、病毒学和免疫学数据的严格评估得出了不可避免的结论：HIV-1 感染必须主要被视为一种粘膜疾病。绝大多数 HIV-1 感染是在阴道和肛交过程中通过粘膜途径感染的，女性感染的频率高于男性。本提案中通过实验解决的许多潜在机制可能涉及游离和细胞相关的 HIV 跨粘膜的传播。穿透性的 HIV-1 会迅速感染上皮下靶细胞（主要是 CD4+ T 细胞），导致粘膜组织中该细胞群的大量消耗，特别是在肠道和其他粘膜器官和组织（包括女性生殖道）中。据推测，由于粘膜 T 细胞耗竭以及由此导致的免疫调节机制崩溃，粘膜防御严重受损，并且主要来自细菌的环境抗原以更高的速率被吸收并激活存在于全身免疫系统中的靶细胞。隔间。此外，对人类进行的大量研究强烈表明，使用基于孕酮的体液避孕药与 HIV-1 感染风险显着增加之间存在显着关联。提交的提案代表了一种综合方法，重点关注粘膜免疫系统的独特部分（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解决：1）女性生殖道中 HIV-1 进入和感染的免疫生物学，涉及识别与 HIV 相关的细胞及其受体。 1 HIV-1感染的进入和易感性，以及抗体在预防HIV-1感染中的作用； 2) 女性生殖道体液反应的显着改变，导致受感染女性意外缺乏 HIV-1 特异性 IgA 反应，以及 HIV-1 诱导的 T 细胞和 B 细胞在粘膜和全身淋巴细胞归巢受体； 3) 基于黄体酮的避孕药对 HIV-1 感染女性粘膜免疫的影响。这些研究的成功取决于能否获得合适的女性群体，正如本提案核心 B 部分所指定和描述的那样。