Role of TNPO3 in HIV-1 Replication

TNPO3 在 HIV-1 复制中的作用

• 批准号: 8709984
• 负责人: Felipe Diaz-Griffero
• 金额: $ 18.54万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8709984
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Agreement; Binding; Capsid; Cations; Cell Nucleus; Cells; Clip; Complex; Cytoplasm; DNA; Development; Future; Genome; Goals; HIV; HIV-1; HIV-2; Human; In Vitro; Infection; Integrase; Maps; Mediating; Molecular; Monitor; Nuclear Import; Nucleotides; Primate Lentiviruses; Process; Proteins; Role; Testing; Viral; Work; novel; public health relevance; receptor; therapeutic target; viral DNA; viral RNA

DESCRIPTION (provided by applicant): TNPO3 is a cellular nuclear import receptor required for HIV-1 infection. Depletion of TNPO3 expression dramatically decreases the infection of primate lentiviruses such as HIV-1, HIV-2 and SIVmac. TNPO3 is essential for early steps on HIV-1 replication. The viral determinant for the requirement of TNPO3 in HIV-1 infection has been genetically mapped to the viral capsid. In agreement with these observations, we have demonstrated that TNPO3 specifically binds the HIV-1 core that is composed of capsid. These results imply that TNPO3 might be interacting with the incoming HIV-1 core early on infection. Depletion of TNPO3 moderately but consistently affects the uncoating process of HIV-1. It is believed that TNPO3 is involved in the nuclear import of the HIV-1 pre-integration complex (PIC); however, this interpretation is in question, as more recent evidence implies that TNPO3 assists HIV-1 replication after nuclear import. Considering the following evidence: 1) depletion of TNPO3 expression affects HIV-1 replication, 2) the viral determinant for the requirement of TNPO3 maps to capsid, 3) TNPO3 binds the HIV-1 capsid, 4) depletion of TNPO3 expression moderately but consistently affects uncoating, and 5) our recent observation that TNPO3 assists HIV-1 replication in an step after nuclear import but before integration. We will test the hypothesis that the binding of TNPO3 to the HIV-1 core in the cytoplasm allows the occurrence of a process that is required for productive infection when the pre-integration complex reaches the nucleus. This proposal will explore the contribution of TNPO3 to HIV-1 integration into the genome by monitoring the two pivotal processes mediated by HIV-1 integrase in the absence of TNPO3, namely 3'-prime processing and DNA strand transfer. Secondly, we will study the role of TNPO3 nuclear-import in HIV-1 infection. The goal of these studies are to understand the mechanism used by TNPO3 to assist HIV-1 replication with the future objective of using TNPO3 as a therapeutic target to block HIV-1 replication. !

描述（由申请人提供）：TNPO 3是HIV-1感染所需的细胞核输入受体。TNPO 3表达的缺失显著降低了灵长类慢病毒如HIV-1、HIV-2和SIVmac的感染。TNPO 3对HIV-1复制的早期步骤至关重要。在HIV-1感染中需要TNPO 3的病毒决定簇已被遗传定位到病毒衣壳。与这些观察结果一致，我们已经证明TNPO 3特异性结合由衣壳组成的HIV-1核心。这些结果意味着TNPO 3可能在感染早期与进入的HIV-1核心相互作用。TNPO 3的消耗适度但持续地影响HIV-1的脱壳过程。据信TNPO 3参与HIV-1整合前复合物（PIC）的核输入;然而，这种解释是有问题的，因为最近的证据表明TNPO 3在核输入后协助HIV-1复制。考虑到以下证据：1） TNPO 3表达影响HIV-1复制，2）TNPO 3需要的病毒决定簇映射到衣壳，3）TNPO 3结合HIV-1衣壳，4）TNPO 3表达的适度消耗但始终影响脱壳，以及5）我们最近观察到TNPO 3在核输入后但在整合前的步骤中协助HIV-1复制。我们将测试的假设，TNPO 3的结合，在细胞质中的HIV-1的核心，允许发生的过程中所需的生产性感染时，前整合复合物到达细胞核。该提案将通过监测在TNPO 3不存在的情况下由HIV-1整合酶介导的两个关键过程，即3 '-引物加工和DNA链转移，来探索TNPO 3对HIV-1整合到基因组中的贡献。第二，研究TNPO 3核输入在HIV-1感染中的作用。这些研究的目的是了解TNPO 3用于辅助HIV-1复制的机制，未来的目标是使用TNPO 3作为阻断HIV-1复制的治疗靶点。!