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）：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。 相关性：对艾滋病毒感染对女性生殖道的生物学和免疫学后果的理解以及荷尔蒙避孕对HIV感染和疾病进展的影响受到限制。阐明艾滋病毒感染和未感染的妇女中涉及的病毒进入，免疫学和激素相互作用所涉及的机制将提供关键的见解，这对预防新感染的策略以及妇女的艾滋病毒相关的发病率和死亡率的降低具有影响。 项目1：女性生殖道的HIV-1进入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）通过粘膜上皮细胞进入； （b）上皮下单核细胞中的感染和随后复制； （c）传递到淋巴结以启动全身感染。为了剖析这些事件，对猕猴和人类生殖组织的研究产生了可变的结果，这可能是因为多个细胞可能参与了事件。此外，猕猴中阻断SIV感染的菌心剂无法阻止女性的感染，甚至增强了女性的感染，强调了对有效的粘膜疫苗的迫切需求。重要的是，由于女性也可以通过直肠暴露获得HIV-1，因此所有高危女性的有效疫苗需要阻止生殖器和直肠粘膜中的HIV-1进入和感染。使用粘膜外植体系统和纯化的粘膜细胞，该建议将阐明HIV-1进入和感染的免疫生物学，并表征抗HIV-1抗体以及基于孕激素的激素对生殖器和直肠粘膜中这些事件的影响。该提案是由四个假设驱动的：（1）HIV-1通过上皮细胞转胞病穿过单层宫颈和直肠上皮，但通过DCS穿过胸腔内的外宫和阴道上皮。 （2）雌性生殖器粘膜选择急性HIV-1感染的R5，基因型限制的病毒； （3）在雌性生殖器粘膜中，巨噬细胞，淋巴细胞和DC允许HIV-1感染，但直肠粘膜中只有淋巴细胞和DC是允许的； （4）IgG（以及可能的IgA）抗HIV-1抗体以及受体类似物和配体抑制了生殖器和直肠粘膜中HIV-1的感染和感染。这些假设将以四个特定目的进行测试：（1）确定细胞，附着分子（S）和受体，无细胞和与细胞相关的R5和X4 HIV-1利用用于进入肠术，颈椎，阴道，阴道和直肠上皮。 （2）确定生殖器粘膜是否选择急性HIV-1感染的R5病毒。 （3）确定女性生殖器粘膜中的HIV-1是否感染淋巴细胞，巨噬细胞和DC，但直肠粘膜中的HIV-1仅感染仅感染淋巴细胞和DC。 （4）确定抗HIV-1（GP41加仑结合结构域，GP41，GP120）抗体和CCR5抗病毒是否阻塞了女性生殖器和直肠粘膜中与细胞无细胞和与细胞相关的R5和X4 HIV-1输入以及X4 HIV-1进入以及X4 HIV-1进入。 相关性：该提案将使用原发性粘膜组织和纯化的粘膜细胞来定义在孕激素基于孕激素的存在和不存在的情况下，人类女性生殖器和直肠组织中HIV-1进入的关键事件和感染。将表征抗体和抗受体剂阻断这些事件的能力，从而为开发粘膜疫苗的开发提供关键信息，以防止女性的生殖器和直肠HIV-1感染。