Cell Motility and GALT HIV Reservoirs

细胞运动性和 GALT HIV 储库

• 批准号: 6798997
• 负责人: GAYLE COCITA BALDWIN
• 金额: $ 15.33万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6798997
• 关键词: HIV infections; acute disease /disorder; biopsy; cell migration; cell motility; chemoattractants; chemotaxis; chronic disease /disorder; clinical research; endoscopy; enzyme linked immunosorbent assay; gastric mucosa; gastrointestinal imaging /visualization; gut associated lymphoid tissue; human immunodeficiency virus 1; human subject; intestinal mucosa; lymphocyte; mucosal immunity; organ culture; virus cytopathogenic effect; virus protein

DESCRIPTION (Provided by applicant): Gastrointestinal associated lymphoid tissue (GALT) contains most of the body's lymphocytes, and therefore constitutes an immense compartment for persistent HIV-1 infection. Moreover, the GALT provides a unique environment for examining how HIV affects cell movement, as well as reconciling two seemingly disparate results: 1) HIV or expression of viral proteins augments cell motility, potentially leading to virus dissemination; and 2) viral proteins and cellular factors acting as chemoattractants may lead to recruitment of other cells to the site of infection and inhibit cell egress, promoting the maintenance of a viral reservoir in the gut. As data from our laboratories would support this dual scenario, we hypothesize that during the acute phase of HIV infection, viral proteins augment the motility of infected gut mucosal lymphoid cells from sites of infection to the periphery. During the chronic stage of HIV infection, viral and cellular chemoattractant factors in the tissue may play a more dominant role, facilitating recruitment of uninfected cells into the gut mucosa. The work outlined in this proposal will directly address this hypothesis by examining the impact of HIV infection on the migration of target cells in the GALT. The Specific Aims are to: 1. Define the acute effects of HIV infection on the motility of GALT immune cells, utilizing: a) isolated gut mucosal mononuclear cells; and b) whole-tissue GALT explant organ cultures from HIV-seronegative individuals. 2. Characterize the viral and cellular chemotactic signals that promote target cell migration, infection, and maintenance of a GALT viral reservoir during chronic HIV infection, using explants from HIV-infected volunteers. The proposed studies explore unique mechanisms by which HIV may disseminate from initial sites of infection, using the novel model system of cultured explants of gut mucosa. Our results may lead to previously unexplored preventive and therapeutic strategies for HIV infection and AIDS.

描述（由申请人提供）：胃肠道相关淋巴组织 (GALT) 含有人体的大部分淋巴细胞，因此构成了持续 HIV-1 感染的巨大隔间。此外，GALT 提供了一个独特的环境来检查 HIV 如何影响细胞运动，并协调两个看似不同的结果：1）HIV 或病毒蛋白的表达增强细胞运动，可能导致病毒传播； 2）作为化学引诱剂的病毒蛋白和细胞因子可能会导致其他细胞募集到感染部位并抑制细胞流出，从而促进肠道内病毒库的维持。由于我们实验室的数据支持这种双重情况，我们假设在 HIV 感染的急性期，病毒蛋白增强了受感染肠粘膜淋巴细胞从感染部位到周围的运动性。在艾滋病毒感染的慢性阶段，组织中的病毒和细胞趋化因子可能发挥更重要的作用，促进未感染细胞招募到肠粘膜中。该提案中概述的工作将通过检查 HIV 感染对 GALT 中靶细胞迁移的影响来直接解决这一假设。具体目标是： 1. 利用： a) 分离的肠粘膜单核细胞，确定 HIV 感染对 GALT 免疫细胞运动的急性影响； b) 来自 HIV 血清阴性个体的全组织 GALT 外植器官培养物。 2. 使用来自 HIV 感染志愿者的外植体，表征慢性 HIV 感染期间促进靶细胞迁移、感染和 GALT 病毒库维持的病毒和细胞趋化信号。拟议的研究利用肠粘膜培养外植体的新型模型系统，探索艾滋病毒从最初感染部位传播的独特机制。我们的结果可能会导致以前未探索过的艾滋病毒感染和艾滋病的预防和治疗策略。