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）：在过去十年中积累的流行病学，病毒学和免疫数据的批判性评估导致不可避免的结论，即必须将HIV-1感染主要视为粘膜疾病。在阴道和肛交期间，粘膜途径遇到了绝对多数HIV-1感染，而女性的频率比男性更高。该提案中实验中解决的许多潜在机制可能与跨粘膜膜的自由和细胞相关的HIV传播有关。穿透HIV-1迅速感染上皮下靶细胞（主要是CD4+ T细胞），导致该细胞群体在粘膜组织中，尤其是肠道和其他粘膜器官和组织，包括女性生殖道，导致该细胞群体的耗尽。据推测，由于粘膜T细胞耗竭以及免疫调节机制的破坏，粘膜防御剂受到严重损害，并且环境抗原（主要是细菌起源）被以更高的速率服用，并在全身免疫室内居住的靶细胞以更高的速度和激活靶细胞。此外，在人类中进行的许多研究强烈表明，使用基于孕激素的体液避孕药与HIV-1感染的风险显着增加之间存在显着关联。提交的建议代表着一种集成的方法，该方法侧重于粘膜免疫系统的独特隔室 - 女性生殖道和HIV -1感染。基于本应用的各个组成部分，整个建议的总体具体目的将解决：1）雌性生殖道中HIV-1进入和感染的免疫生物学，鉴于鉴定细胞及其对HIV-1输入的细胞及其受体对HIV-1感染涉及的受体，以及抗体在HIV-1感染中的作用； 2）在受感染女性中HIV-1特异性IgA反应的意外缺乏以及HIV-1诱导的T和B细胞中T和B细胞的变化相对于粘膜和全身性淋巴细胞归因受体的表达，HIV-1特异性IgA反应的意外缺乏，体液反应发生了明显变化； 3）基于孕激素的避孕药对HIV-1感染妇女的粘膜免疫的影响。这些研究的成功取决于本提案的核心B部分中指定和描述的适当妇女同类群体的可及性。