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: 7680723
• 负责人: JIRI F MESTECKY
• 金额: $ 200.02万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7680723
• 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. RELEVANCE: The understanding of the biological and immunological consequences of HIV infection on the female genital tract and the effects of hormonal contraception on HIV infection and disease progression is limited. Elucidation of the mechanisms involved in viral entry, immunological, and hormonal interactions in HIV infected and uninfected women will provide critical insight, with implications in the design of strategies for the prevention of new infections and the reduction of HIV-associated morbidity and mortality in women. PROJECT 1: Immunobiology of HIV-1 Entry and Infection in the Female Genital Tract (Project Leader: Smith, P) PROJECT 1 DESCRIPTION (provided by applicant): The immunobiology of HIV-1 infection in the female genital tract involves three major events: (a) Entry through the mucosal epithelium; (b) Infection and subsequent replication in subepithelial mononuclear cells; and (c) Delivery to lymph nodes to initiate systemic infection. To dissect these events, studies of macaque and human genital tissues have yielded variable results, likely because multiple cells may be involved in the events. Moreover, microbicidal agents that block SIV infection in macaques fail to block, or even enhance, infection in women, underscoring the urgent need for an effective mucosal vaccine. Importantly, because women may also acquire HIV-1 through rectal exposure, an effective vaccine for all at-risk women needs to block HIV-1 entry and infection in both genital and rectal mucosa. Using a mucosal explant system and purified mucosal cells, this proposal will elucidate the immunobiology of HIV-1 entry and infection and characterize the effect of anti-HIV-1 antibodies and progesterone-based hormonal agents on these events in genital and rectal mucosa. The proposal is driven by four Hypotheses: (1) HIV-1 crosses the monostratified endocervical and rectal epithelium by epithelial cell transcytosis but crosses pleuristratified ectocervical and vaginal epithelium via DCs; (2) Female genital mucosa selects the R5, genotypically restricted viruses that characterize acute HIV-1 infection; (3) In female genital mucosa, macrophages, lymphocytes and DCs are permissive to HIV-1 infection, but in rectal mucosa only lymphocytes and DCs are permissive; and (4) HIV- 1 entry and infection in genital and rectal mucosae are inhibited by IgG (and possibly IgA) anti-HIV-1 antibodies, and receptor analogs and ligands. These hypotheses will be tested with four Specific Aims: (1) Determine the cell(s), attachment molecule(s) and receptor(s) that cell-free and cell-associated R5 and X4 HIV-1 utilizes to enter the endocervical, ectocervical, vaginal and rectal epithelium. (2) Determine whether genital mucosa selects the R5 viruses that characterize acute HIV-1 infection. (3) Determine whether HIV-1 in female genital mucosa infects lymphocytes, macrophages and DCs but in rectal mucosa infects only lymphocytes and DCs. (4) Determine whether anti-HIV-1 (gp41 GalCer-binding domain, gp41, gp120) antibodies and CCR5 anti-virals block cell-free and cell-associated R5 and X4 HIV-1 entry and target cell infection in female genital and rectal mucosa. RELEVANCE: This proposal will use primary mucosal tissues and purified mucosal cells to define the key events in HIV-1 entry and infection in human female genital and rectal tissue in the presence and absence of progesterone based hormonal agents. The ability of antibodies and anti-receptor agents to block these events will be characterized, thereby providing critical information for the development of a mucosal vaccine to prevent genital and rectal HIV-1 infection in women.

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。 相关性：对于 HIV 感染对女性生殖道的生物学和免疫学后果以及激素避孕对 HIV 感染和疾病进展的影响的了解有限。阐明感染艾滋病毒和未感染女性的病毒进入、免疫和激素相互作用的机制将提供重要的见解，对预防新感染和降低女性艾滋病毒相关发病率和死亡率的策略设计具有重要意义。 项目 1：HIV-1 进入女性生殖道和感染的免疫生物学 （项目负责人：史密斯，P） 项目 1 描述（由申请人提供）：女性生殖道中 HIV-1 感染的免疫生物学涉及三个主要事件： (a) 通过粘膜上皮进入； (b) 上皮下单核细胞的感染和随后的复制； (c)递送至淋巴结以引发全身感染。为了剖析这些事件，对猕猴和人类生殖组织的研究得出了不同的结果，可能是因为这些事件可能涉及多个细胞。此外，阻断猕猴 SIV 感染的杀菌剂无法阻断甚至增强女性感染，这凸显了对有效粘膜疫苗的迫切需要。重要的是，由于女性也可能通过直肠接触感染 HIV-1，因此针对所有高危女性的有效疫苗需要阻止 HIV-1 进入生殖器和直肠粘膜并进行感染。该提案将利用粘膜外植体系统和纯化的粘膜细胞，阐明 HIV-1 进入和感染的免疫生物学，并表征抗 HIV-1 抗体和基于孕激素的激素药物对生殖器和直肠粘膜这些事件的影响。该提议由四个假设驱动：(1) HIV-1 通过上皮细胞转胞吞作用穿过单层子宫颈内膜和直肠上皮，但通过 DC 穿过胸膜层子宫颈外皮和阴道上皮； (2) 女性生殖器粘膜选择R5基因型限制性病毒，其特征是急性HIV-1感染； (3)在女性生殖器粘膜中，巨噬细胞、淋巴细胞和DC允许HIV-1感染，但在直肠粘膜中，只有淋巴细胞和DC允许感染； (4)HIV-1进入生殖器和直肠粘膜并受到IgG(可能还有IgA)抗HIV-1抗体以及受体类似物和配体的抑制。这些假设将通过四个具体目标进行检验：(1) 确定无细胞和细胞相关的 R5 和 X4 HIV-1 用于进入宫颈内膜的细胞、附着分子和受体，宫颈外、阴道和直肠上皮。 (2)确定生殖器粘膜是否选择表征急性HIV-1感染的R5病毒。 (3)确定女性生殖粘膜中的HIV-1是否感染淋巴细胞、巨噬细胞和DC，而直肠粘膜中的HIV-1仅感染淋巴细胞和DC。 (4) 确定抗 HIV-1（gp41 GalCer 结合结构域、gp41、gp120）抗体和 CCR5 抗病毒药物是否能阻断女性生殖器和女性生殖器中无细胞和细胞相关的 R5 和 X4 HIV-1 进入和靶细胞感染。直肠粘膜。 相关性：该提案将使用原代粘膜组织和纯化的粘膜细胞来确定在存在或不存在基于孕酮的激素制剂的情况下，人类女性生殖器和直肠组织中 HIV-1 进入和感染的关键事件。抗体和抗受体剂阻断这些事件的能力将得到表征，从而为开发粘膜疫苗以预防女性生殖器和直肠 HIV-1 感染提供关键信息。