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的细胞储存库，使病毒保持在具有复制能力的形式，使持续感染永久化。人们对潜伏感染的CD4 T细胞和单核/巨噬细胞的关注较多，然而，对滤泡树突状细胞（FDC）的HIV储存库的关注很少，尽管它是体内最大的储存库之一，据估计每克淋巴组织含有1.5 × 108个病毒RNA拷贝。我们的工作假设是，fdc是保存在微环境中的传染性病毒的长期储存库，该微环境是HIV传播和繁殖的理想组织。我们之前的研究表明，fdc捕获的HIV: 1)具有高度传染性，即使在存在强效中和抗体的情况下仍具有高度传染性；ii)在不需要活跃病毒感染/复制的情况下以感染性形式维持数月。