Follicular Dendritic Cells and HIV Pathogenesis

滤泡树突状细胞和 HIV 发病机制

• 批准号: 7073866
• 负责人: Gregory F. Burton
• 金额: $ 35.13万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7073866
• 关键词: AIDS; chemokine; chemokine receptor; clinical research; dendritic cells; helper T lymphocyte; host organism interaction; human immunodeficiency virus; human subject; latent virus infection; lymphatic tissue; tissue /cell culture; virulence; virus cytopathogenic effect; virus genetics

A major concern in the treatment of HIV/AIDS is the establishment of long-term cellular reservoirs where virus is maintained in a replication-competent form that perpetuates persisting infection. Much attention has been focused on latently infected CD4 T cells, and to a lesser extent monocytes/macrophages, however, little attention has been given to the follicular dendritic cell (FDC) reservoir of HIV even though it is one of the largest reservoirs in the body estimated to contain 1.5xl08 copies of viral RNA per gram of lymphoid tissue. Our working hypothesis is that FDCs are a long-term reservoir of infectious virus preserved in a microenvironment that is ideally organized for transmission and propagation of HIV. Our previous studies indicate that FDC-trapped HIV: i) is highly infectious and remains so even in the presence of potent neutralizing antibodies; and ii) is maintained in an infectious form for months with no requirement for active viral infection/replication. Progress during the last funding period indicated that FDCs contribute to a highly permissive microenvironment for virus transmission and propagation by: i) increasing the level of CXCR4 expression on surrounding germinal center (GC) CD4 T cells making them highly susceptible to infection with X4-tropic HIV; ii) producing chemokines (e.g. CXCL13) that attract GC T cells while providing signaling that inhibits migration away from the FDCs; and iii) increasing HIV transcription in a TNF dependent manner. We have also found that attempts to destroy the FDC reservoir of HIV by blocking signals needed for development and maintenance of FDCs fails to ablate this important source of infectious virus. This renewal application seeks to extend our studies on the FDC-HIV reservoir by: i) determining the genetic relatedness of FDC trapped virus in one secondary, lymphoid tissue site with that found in other sites sampled at the same time; ii) establishing the genetic relatedness of virus trapped on FDCs over time in the same patient; iii) characterizing FDC-HIV interactions that contribute to viral pathogenesis; and iv) identifying contributions of the FDC-GC microenvironment to HIV transmission and expression.

治疗艾滋病毒/艾滋病的一个主要问题是建立长期细胞储存库，使病毒保持在有复制能力的形式，从而使持续感染永久化。很多注意力都集中在潜伏感染的 CD4 T 细胞上，其次是单核细胞/巨噬细胞，然而，很少有人关注 HIV 的滤泡树突状细胞 (FDC) 储存库，尽管它是人类最大的储存库之一。据估计，身体每克淋巴组织含有1.5x108个病毒RNA拷贝。我们的工作假设是，FDC 是传染性病毒的长期储存库，保存在一个非常适合 HIV 传播和传播的微环境中。我们之前的研究表明，FDC 捕获的 HIV： i) 具有高度传染性，并且即使存在强效中和抗体，传染性仍然如此； ii) 保持传染性形式数月，不需要活跃的病毒感染/复制。 上一个资助期间的进展表明，固定发展公司有助于高度宽松的 通过以下方式改善病毒传播和繁殖的微环境： i) 提高 CXCR4 的水平 周围生发中心 (GC) CD4 T 细胞的表达使其高度易感 感染 X4 嗜性 HIV； ii) 产生吸引 GC T 细胞的趋化因子（例如 CXCL13），同时 提供抑制 FDC 迁移的信号； iii) 以 TNF 依赖性方式增加 HIV 转录。我们还发现，通过阻断 FDC 发育和维持所需的信号来破坏 HIV FDC 储存库的尝试未能消除这一重要的传染性病毒来源。这一更新申请旨在通过以下方式扩展我们对 FDC-HIV 储存库的研究： i) 确定在一个二级淋巴组织部位中捕获的 FDC 病毒与同时采样的其他部位中发现的病毒的遗传相关性； ii) 确定同一患者体内随时间推移固定在 FDC 上的病毒的遗传相关性； iii) 表征导致病毒发病机制的 FDC-HIV 相互作用； iv) 确定 FDC-GC 微环境对 HIV 传播和表达的贡献。