Immunopathogenesis of HIV in the Female Reproductive Tract

项目3的目标是解决与粘膜相关淋巴细胞的作用有关的关键问题， 女性生殖道组织（FRT）在HIV发病机制中的作用。我们的总体假设是， FRT的免疫微环境影响HIV疾病进展。我们将测试这个假设， 三个具体目标。在具体目标1中，我们将定义衰老对先天和适应性细胞介导的 血液和女性生殖道中的免疫反应，以及这些免疫反应的潜在影响 对HIV发病机制和疾病进展的影响。免疫功能的性别差异可能是 与男性和女性性激素的调节有关。生殖老化和更年期，其特征是 通过雌激素水平的下降，可能会影响雌激素反应性免疫细胞的功能，包括T淋巴细胞和B淋巴细胞 和NK细胞。我们将检验生殖衰老改变细胞介导的 FRT的免疫和免疫微环境，可能影响艾滋病毒疾病的进程。 在具体目标2中，我们将确定HIV感染对女性粘膜组织的影响 生殖道和胃肠道的个体在疾病谱的两端，对比 自然的HIV控制者和停止治疗的进展者。大多数艾滋病毒传播是通过性行为发生的。 通过子宫颈、阴道和直肠的粘膜表面接触。虽然这些组织是艾滋病毒的关键 传播和发病机制，在这些网站的宿主-病毒相互作用的研究是有限的。我们 假设HIV感染者生殖粘膜组织的结构和功能变化 女性可以与胃肠道中观察到的相似，特别是在参数方面 如CD 4记忆亚群耗竭、免疫激活和调节性T细胞。在具体目标3中， 我们将确定HIV感染对FRT和胃肠道粘膜组织的影响， 血液CD 4细胞恢复率低与高的HAART接受者。个体对HAART的反应各不相同 10-30%的治疗患者从未达到CD 4再增殖的期望阈值。我们 假设HAART诱导的FRT中CD 4细胞的重建可能落后于外周血， 血液，平行于在胃肠道中观察到的延迟重建。我们将确定 HAART接受者FRT和GI道粘膜组织上的HIV感染， 恢复血液中的CD 4细胞。总之，这些研究应该提供了许多新的见解的作用， HIV发病机制中的上FRT。这些研究是高度合作的，将涉及的PI 项目1和2作为共同研究者或合作者。

The goal of Project 3 is to address key questions with respect to the role of mucosa-associated lymphoid tissues of the female reproductive tract (FRT) in HIV pathogenesis. Our overall hypothesis is that changes in the immune microenvironment of the FRT affect HIV disease progression. We will test this hypothesis in three specific aims. In Specific Aim 1, we will define the effects of aging on innate and adaptive cellmediated immune responses in blood and the female reproductive tract, and the potential impact of these effects on HIV pathogenesis and disease progression. Gender-based differences in immune function may be related to regulation by male and female sex hormones. Reproductive aging and menopause, characterized by a decline of estrogen levels, may affect function of estrogen-responsive immune cells, including T- and Blymphocytes and NK cells. We will test the hypothesis that reproductive aging alters cell-mediated immunity and the immune microenvironment of the FRT, potentially influencing HIV disease course. In Specific Aim 2, we will determine the effects of HIV infection on mucosal tissues of the female reproductive and gastrointestinal tracts in individuals at opposite ends of the disease spectrum, contrasting natural HIV controllers with off-treatment progressors. The majority of HIV transmission occurs via sexual contact across the mucosal surfaces of the cervix, vagina, and rectum. Although these tissues are key to HIV transmission and pathogenesis, studies of host-virus interactions at these sites have been limited. We hypothesize that the structural and functional changes in the reproductive mucosal tissues of HIVinfected women may parallel those observed in the Gl tract, in particular with respect to parameters such as CD4 memory subset depletion, immune activation, and regulatory T cells. In Specific Aim 3, we will define the effects of HIV infection on mucosal tissues of the FRT and the gastrointestinal tract in HAART recipients with low versus high recovery of blood CD4 cells. Individual responses to HAART vary significantly, and 10-30% of treated patients never reach the desired threshold of CD4 repopulation. We hypothesize that HAART-induced reconstitution of CD4 cells in the FRT may lag behind peripheral blood, paralleling the delayed reconstitution observed in the Gl tract. We will determine the effects of HIV infection on mucosal tissues of the FRT and the Gl tract in HAART recipients with low versus high recovery of blood CD4 cells. Taken together, these studies should provide many new insights into the role of the upper FRT in HIV pathogenesis. These studies are highly collaborative and will involve the Pis of Projects 1 and 2 as Co-Investigators or Collaborators.