Follicular dendritic cells & HIV Pathogenesis

滤泡树突状细胞

• 批准号: 6631833
• 负责人: Gregory F. Burton
• 金额: $ 27.72万
• 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 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6631833
• 关键词: CD4 molecule; HIV infections; T lymphocyte; dendritic cells; disease reservoirs; human immunodeficiency virus; human tissue; laboratory mouse; latent virus infection; microorganism immunology; pathologic process; virus infection mechanism; virus replication

A major concern in HIV pathogenesis is the establishment of long-term reservoirs of replication-competent virus. Although much attention has been directed to the latently infected T cell reservoir of HIV, less is known about the reservoir of infectious virus on follicular dendritic cells (FDC). FDCs trap and retain large quantities of HIV and throughout much of disease, viral replication persists in secondary lymphoid tissues surrounding germinal centers where FDCs reside. Our working hypothesis is that FDC represent a dangerous, long-term reservoir of highly infectious HIV. Our previous work indicated that HIV trapped on FDC as immune complexes is infectious and that FDC permit infection by this virus even in the presence of large amounts of otherwise neutralizing antibodies. During the previous finding period, we extended this work and found that FDC maintain HIV in an infectious state for many months in the complete absence of virus replication. Furthermore, FDCs potentiate the amount of HIV infection/replication in CD4 T cell cultures and at least part of this effect is attributable to FDC sparing of bystander T cells from undergoing HIV-induced apoptosis. We propose to extend this work and examine other contributions of FDCs that increase infection as well as to characterize FDC-HIV binding interactions. This proposal seeks to determine the mechanism(s) used by FDC to augment HIV infection/replication in CD4-bearing T cells (aim 1). We also seek to determine if FDC can "archive" infectious HIV while being exposed to mutants or new populations of HIV(aim 2). Finally, we seek to determine if the FDC reservoir can be destroyed and, if so, to examine the fate of FDC-trapped virus (aim 3). Because virus replication continues even under HAART, we reason that HIV on FDCs is constantly replenished and this virus could cause re-infection on cessation of drug or other selective therapy. A better understanding of HIV-FDC interactions should help in designing intervention strategies that effectively target this important reservoir.

HIV发病机理的主要关注点是建立具有复制能力的病毒的长期储藏。尽管已经对艾滋病毒的潜在感染的T细胞储量进行了很多关注，但对卵泡树突状细胞（FDC）的传染病储层（FDC）的了解较少。 FDCS陷阱并保留大量的HIV以及在大部分疾病中，病毒复制持续存在于FDCS居住的生发中心周围的继发性淋巴组织中。我们的工作假设是，FDC代表了高度传染性艾滋病毒的危险，长期的水库。我们以前的工作表明，将HIV捕获在FDC上，因为免疫复合物具有感染性，即使在大量其他原本中和抗体的情况下，FDC也允许该病毒感染该病毒。在上一个发现期间，我们扩展了这项工作，发现FDC在完全没有病毒复制的情况下将HIV保持在传染性状态多个月。此外，FDC会增强CD4 T细胞培养物中的HIV感染/复制量，并且至少部分这种作用归因于FDC在患HIV诱导的细胞凋亡中对旁观者T细胞的保留。我们建议扩展这项工作，并检查FDC的其他贡献，这些FDC会增加感染以及表征FDC-HIV结合相互作用。该提案旨在确定FDC用来增强CD4带有T细胞中HIV感染/复制的机制（AIM 1）。我们还试图确定FDC在暴露于突变体或新的HIV种群的同时（AIM 2）时是否可以“存档”感染性艾滋病毒。最后，我们试图确定FDC储层是否可以被破坏，如果是，则检查FDC捕获的病毒的命运（AIM 3）。由于病毒复制甚至在HAART的领导下仍在继续，因此我们认为FDC上的HIV不断补充，该病毒可能会引起药物停止或其他选择性疗法的再感染。对HIV-FDC相互作用的更好理解应有助于设计有效针对这一重要储层的干预策略。