Follicular dendritic cells & HIV Pathogenesis

HIV发病机制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。尽管人们对HIV潜伏感染的T细胞储存库关注甚多，但对滤泡树突状细胞（FDC）上的感染性病毒储存库了解甚少。fdc捕获并保留了大量的HIV病毒，在疾病的大部分过程中，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是一个危险的、长期的高传染性艾滋病毒储存库。我们之前的工作表明，作为免疫复合物被困在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将HIV维持在感染状态数月。此外，FDC增强了CD4 T细胞培养物中HIV感染/复制的数量，至少部分原因是FDC保护了旁观者T细胞免受HIV诱导的凋亡。我们建议扩展这项工作，并检查fdc增加感染的其他贡献，以及表征FDC-HIV结合相互作用。本研究旨在确定FDC在携带cd4的T细胞中增强HIV感染/复制的机制（目的1）。我们还试图确定FDC是否可以在暴露于突变体或新的HIV群体时“存档”传染性HIV（目标2）。最后，我们试图确定是否可以摧毁FDC储存库，如果可以，则检查捕获FDC的病毒的命运（目标3）。由于即使在HAART下病毒复制仍在继续，我们推断fdc上的艾滋病毒不断得到补充，这种病毒可能在停止药物或其他选择性治疗后再次感染。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层的干预策略。

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.