Immunopathogenesis of HIV in the Female Reproductive Tract

女性生殖道中艾滋病毒的免疫发病机制

• 批准号: 7684933
• 负责人: Barbara L. Shacklett
• 金额: $ 37.76万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684933
• 关键词: Address; Affect; Aging; Antibodies; B-Lymphocytes; Blood; CD4 Positive T Lymphocytes; Cells; Cellular Immunity; Cervix Uteri; Chronic; Clinical; Clinical Research; Collaborations; Confocal Microscopy; Defense Mechanisms; Disease; Disease Progression; Enhancers; Estrogen Receptors; Estrogens; Female; Fibrosis; Gastrointestinal tract structure; Gender; Gene Expression Profile; Genital system; Genitourinary system; Goals; Gonadal Steroid Hormones; Gut associated lymphoid tissue; HIV; HIV Infections; Highly Active Antiretroviral Therapy; Immune; Immune response; Immunohistochemistry; Immunologic Markers; Immunology; Individual; Inflammation; Institutes; Laboratories; Light; Link; Lymphoid Tissue; Measures; Mediating; Memory; Menopause; Menstrual cycle; Mucous Membrane; Natural Killer Cells; Output; Pathogenesis; Patients; Principal Investigator; Progesterone; Recovery; Rectum; Regulation; Research Design; Research Personnel; Role; Sampling; San Francisco; Site; Specimen; Surface; T-Cell Depletion; T-Lymphocyte; Testing; Time; Tissues; Vagina; Viral; Viral Load result; Woman; age effect; base; cell mediated immune response; cell type; fighting; gastrointestinal; immune function; insight; lymph nodes; macrophage; male; mucosa-associated lymphoid tissue; peripheral blood; reconstitution; reproductive; response; transmission process; virology; virus host interaction

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.

项目3的目标是解决与粘膜相关淋巴的作用有关的关键问题 HIV发病机制中的女性生殖道组织(FRT)。我们的总体假设是， FRT的免疫微环境影响HIV疾病的进展。我们将在以下方面测试这一假设 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调节的影响 血液和女性生殖道中的免疫反应以及这些反应的潜在影响 对HIV发病机制和疾病进展的影响。基于性别的免疫功能差异可能是 与男性和女性性激素的调节有关。生殖老化和更年期，特征 通过雌激素水平的下降，可能会影响雌激素反应免疫细胞的功能，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假设 免疫和FRT的免疫微环境，可能影响艾滋病毒的病程。 在特定的目标2中，我们将确定艾滋病毒感染对女性粘膜组织的影响 处于疾病谱相反两端的个体的生殖道和胃肠道，形成对比 带有非治疗进展者的天然艾滋病毒控制者。大多数艾滋病毒传播是通过性行为传播的 通过宫颈、阴道和直肠的粘膜表面接触。尽管这些组织是HIV的关键 在传播和致病机制方面，对这些部位的宿主-病毒相互作用的研究一直很有限。我们 HIV感染者生殖黏膜组织结构和功能改变的假说 女性可能与在Gl区观察到的相似，特别是在参数方面 例如，CD4记忆亚群耗尽、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 HAART受者的血液CD4细胞回收率低与高。对HAART的个人反应各不相同 值得注意的是，10-30%的接受治疗的患者从未达到理想的CD4再繁殖阈值。我们 假设HAART诱导的FRT中的CD4细胞重建可能滞后于外周 血液，与在胃肠道观察到的延迟重建平行。我们将确定 HAART低剂量与高剂量HAART受者FRT和Gl道粘膜组织中的HIV感染 血液中CD4细胞的恢复。综上所述，这些研究应该会提供许多新的见解，以了解 上段FRT在HIV发病机制中的作用这些研究是高度协作的，将涉及PIS 项目1和2作为联合调查员或合作者。