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发病机制的一个主要问题是具有复制能力的病毒长期储存库的建立。尽管人们对潜伏感染的 HIV T 细胞储存库给予了很多关注，但对滤泡树突状细胞 (FDC) 上感染性病毒储存库的了解却很少。 FDC 捕获并保留大量 HIV，并且在许多疾病过程中，病毒复制持续存在于 FDC 所在的生发中心周围的次级淋巴组织中。我们的工作假设是，FDC 是高传染性 HIV 的危险的长期储存库。我们之前的工作表明，作为免疫复合物捕获在 FDC 上的 HIV 具有传染性，并且即使存在大量其他中和抗体，FDC 也允许这种病毒感染。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使 HIV 保持感染状态达数月之久。此外，FDC 增强了 CD4 T 细胞培养物中 HIV 感染/复制的数量，并且这种效应的至少部分归因于 FDC 使旁观者 T 细胞免于经历 HIV 诱导的细胞凋亡。我们建议扩展这项工作并研究 FDC 对增加感染的其他贡献以及表征 FDC-HIV 结合相互作用。该提案旨在确定 FDC 用于增强携带 CD4 的 T 细胞中的 HIV 感染/复制的机制（目标 1）。我们还试图确定 FDC 在暴露于 HIV 突变体或新群体时是否可以“存档”感染性 HIV（目标 2）。最后，我们试图确定 FDC 储存库是否可以被破坏，如果可以，则检查 FDC 捕获的病毒的命运（目标 3）。因为即使在HAART下病毒复制仍在继续，我们推断FDC上的HIV会不断补充，并且这种病毒可能会在停止药物或其他选择性治疗时导致再次感染。更好地了解 HIV-FDC 相互作用应有助于设计有效针对这一重要储存库的干预策略。