Immunologic Uniqueness of the Female Genital Tract in HIV Pathogenesis

描述（由申请人提供）：对过去十年积累的流行病学、病毒学和免疫学数据的批判性评估导致不可避免的结论，即HIV-1感染必须主要被认为是一种粘膜疾病。绝大多数HIV-1感染是在阴道性交和肛交时通过粘膜途径感染的，女性感染的频率高于男性。许多潜在的机制，在这个提议的实验中，可能涉及到自由和细胞相关的HIV跨粘膜传播。穿透性HIV-1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显著广泛耗竭，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细胞耗损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）以更高的速率被吸收，并激活驻留在全身免疫室的靶细胞。此外，在人类中进行的大量研究强烈表明，使用以黄体酮为基础的体液避孕药与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，专注于粘膜免疫系统的一个独特隔间-女性生殖道-和HIV-1感染。基于该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进入和感染易感性的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)女性生殖道体液反应的显著改变与感染女性hiv -1特异性IgA反应的意外缺乏有关，以及hiv -1诱导的T细胞和B细胞中粘膜和全身淋巴细胞归巢受体表达的变化；3)黄体酮类避孕药对HIV-1感染妇女粘膜免疫的影响。这些研究的成功取决于是否有合适的妇女群体，如本提案核心B部分所规定和描述的那样。

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.