Project 2 - Identification of the source of viral rebound using SIV proviral genome analysis

摘要 制定成功的策略以延缓并最终防止病毒反弹的关键 阻断治疗是为了找出病毒反弹的来源和机制。正在进行中 关于反弹来源的争论包括1)是CD4+T细胞还是组织巨噬细胞 是反弹的主要来源，2)淋巴组织中正在进行的复制周期 组织有助于反弹，3)HIV-1感染是否可能主动驱动克隆性扩张 通过整合到与增殖相关的基因中，感染细胞的数量。我们建议在这里探索 在使用我们开发的一项新技术的SIV模型中的协作研究中的这些问题 一群人。利用HIV-1前病毒的全长、单基因组测序，我们最近展示了 绝大多数(95%)患者细胞中的HIV-1前体是有缺陷的。这一发现 极大地增加了对诸如反跳病毒血症的来源、感染的可能性 治疗过程中的病毒进化，以及克隆性扩张在病毒持久性中的作用。在……里面 初步研究表明，大多数SIV前病毒也是有缺陷的。通过专注于 那些没有缺陷的前病毒，我们将能够更好地理解细胞来源 防止病毒反弹，并解决关于治疗期间病毒复制的争议 以及通过感染细胞的增殖来扩大储存库。这项研究将在#年进行。 与霍普金斯大学的同事合作，他们将采用其他具有复制能力的新方法 在申请中描述的治疗猕猴队列中的SIV。把这些研究放在一起 应该为病毒反弹的来源提供新的见解。

Abstract The key to developing successful strategies to delay and ultimately prevent viral rebound upon treatment interruption is to identify the source and mechanisms of viral rebound. Ongoing debates regarding the source of rebound include 1) whether CD4+ T cells or tissue macrophages are the dominant source of rebound, 2) whether ongoing cycles of replication in the lymphoid tissue contribute to rebound, 3) whether HIV-1 infection may actively drive the clonal expansion of infected cells through integration into proliferation-related genes. We propose here to explore these issues in collaborative studies in the SIV model using a new technology developed by our group. Using full length, single genome sequencing of HIV-1 proviruses, we have recently shown that the vast majority (>95%) of HIV-1 proviruses in patient cells are defective. This discovery greatly complicates analysis of issues such as the source of rebound viremia, the possibility of ongoing viral evolution during treatment, and the role of clonal expansion in viral persistence. In preliminary studies, we have shown that most SIV proviruses are also defective. By focusing on those proviruses that are not defective, we will be able to better understand the cellular sources of viral rebound and to address controversies regarding ongoing viral replication during treatment and reservoir expansion through proliferation of infected cells. This studies will be carried out in conjunction with Hopkins colleagues who will employ other novel assays for replication-competent SIV in the cohorts of treated macaques described in the application. Together these studies should provide new insights into the sources of viral rebound.