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发病机制中的一个主要问题是建立具有复制能力的病毒的长期储存库。虽然HIV的潜伏感染T细胞库已经引起了很多关注，但关于滤泡树突状细胞(FDC)上的传染性病毒库的研究却知之甚少。FDCs捕获并保留大量的艾滋病毒，在大部分疾病中，病毒复制持续存在于FDDC所在生发中心周围的次级淋巴组织中。我们的工作假设是，FDC代表着一个危险的、长期的高传染性艾滋病毒宿主。我们以前的工作表明，捕获在FDC上的HIV作为免疫复合体是有传染性的，FDC允许这种病毒感染，即使存在大量的中和抗体。在之前的发现期间，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保持在感染状态数月。此外，FDC增强了CD4T细胞培养中HIV的感染/复制量，至少部分原因是FDC避免了旁观者T细胞经历HIV诱导的凋亡。我们建议扩展这项工作，检查FDCs增加感染的其他贡献，以及表征FDC与HIV的结合作用。这项建议试图确定食品和药物委员会用来增强携带艾滋病毒的T细胞感染/复制艾滋病毒的机制(S)(目标1)。我们还试图确定FDC是否可以在暴露于艾滋病毒突变体或新的艾滋病毒种群的情况下“存档”传染性艾滋病毒(目标2)。最后，我们试图确定FDC水库是否可以被摧毁，如果可以，则检查FDC捕获的病毒的命运(目标3)。由于病毒复制即使在HAART下仍在继续，我们推测FDDC上的HIV不断补充，这种病毒可能会在停止药物或其他选择性治疗后导致再次感染。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蓄者的干预战略。