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

项目 2 - 使用 SIV 原病毒基因组分析识别病毒反弹的来源

• 批准号: 9322142
• 负责人: ROBERT F SILICIANO
• 金额: $ 33.02万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-23 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9322142
• 关键词: Address; Affect; Anatomy; Animals; Antibodies; Biological Assay; Biological Markers; Blood; CD4 Positive T Lymphocytes; Cell Compartmentation; Cells; Clonal Expansion; DNA; Evolution; Failure; Frequencies; Genes; Genome; HIV; HIV-1; Infection; Interruption; Lead; Length; Light; Lymphoid Tissue; Macaca; Maps; Mature T-Lymphocyte; Methods; Modeling; Patients; Phylogenetic Analysis; Production; Proviruses; Recovery; Role; SIV; Source; Thymus Gland; Time; Tissues; Viral; Viremia; Virion; Virus Replication; cohort; experimental study; genome analysis; genome sequencing; insight; integration site; macrophage; new technology; novel; peripheral blood; prevent; reconstitution; viral rebound

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.

抽象的 制定成功策略延迟并最终防止病毒反弹的关键 治疗中断时是确定病毒反弹的来源和机制。正在进行 关于反弹来源的辩论包括1）CD4+ T细胞还是组织巨噬细胞 是反弹的主要来源，2）淋巴机中的复制循环是否正在 组织有助于反弹，3）HIV-1感染是否可以主动驱动克隆膨胀 感染细胞通过整合到增殖相关基因中。我们在这里建议探索 SIV模型中的协作研究中的这些问题使用我们的新技术 团体。使用HIV-1病毒的全长，单基因组测序，我们最近显示了 患者细胞中的绝大多数HIV-1病毒（> 95％）是有缺陷的。这个发现 对诸如反弹病毒血症之类的问题的分析非常复杂，可能性 治疗过程中持续的病毒演化以及克隆扩张在病毒持久性中的作用。在 初步研究，我们表明大多数SIV病毒也有缺陷。通过关注 那些没有缺陷的病毒，我们将能够更好地了解蜂窝源 病毒反弹并解决有关治疗过程中持续病毒复制的争议 以及通过受感染细胞的扩散来扩展储层。这项研究将在 与霍普金斯同事的结合，他们将采用其他新颖的测定法进行复制能力 应用程序中描述的经过处理的猕猴的SIV。共同研究 应该为病毒反弹来源提供新的见解。