Role of TNPO3 in HIV-1 Replication

TNPO3 在 HIV-1 复制中的作用

• 批准号: 9210143
• 负责人: Felipe Diaz-Griffero
• 金额: $ 2.34万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9210143
• 关键词: Role; TNPO3; HIV; Replication

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）：TNPO3是HIV-1感染所需的细胞核进口受体。 TNPO3表达的耗竭大大降低了灵长类动病毒（例如HIV-1，HIV-2和SIVMAC）的感染。 TNPO3对于HIV-1复制的早期步骤至关重要。 TNPO3在HIV-1感染中需要的病毒决定因素已在遗传上映射到病毒式衣壳。与这些观察结果一致，我们已经证明TNPO3特异性结合了由衣壳组成的HIV-1核心。这些结果表明，TNPO3可能在感染早期与传入的HIV-1核心相互作用。 TNPO3的耗竭适度但始终如一地影响HIV-1的不涂层过程。据认为，TNPO3参与了HIV-1前整合复合物（PIC）的核进口。但是，这种解释是有问题的，因为最近的证据表明，TNPO3有助于核进口后的HIV-1复制。考虑以下证据：1） 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.我们将检验以下假设：TNPO3与细胞质中HIV-1核的结合允许在预一体化复合物到达核时发生生产感染所需的过程。该建议将通过监测没有TNPO3的HIV-1积分介导的两个关键过程，即3'-PRIME处理和DNA链传递，探讨TNPO3对HIV-1整合到基因组中的贡献。其次，我们将研究TNPO3核象征在HIV-1感染中的作用。这些研究的目的是了解TNPO3用来帮助HIV-1复制的机制，并将将TNPO3用作阻止HIV-1复制的治疗靶标的未来目标。呢