Novel host proteins in the HIV-1 preintegration complexes

HIV-1预整合复合物中的新型宿主蛋白

• 批准号: 8513257
• 负责人: Li Wu
• 金额: $ 21.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-20 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513257
• 关键词: Address; Affect; Anti-HIV Agents; Binding Proteins; Biological Assay; CD4 Positive T Lymphocytes; Cell Survival; Cells; Complementary DNA; Complex; DNA; DNA Repair; Drug Targeting; Drug resistance; Funding Mechanisms; Goals; HIV; HIV Infections; HIV-1; Human; Individual; Infection; Integrase; Knowledge; Length; Lentivirus Vector; Life; Measures; Messenger RNA; Nature; Nuclear Import; Nuclear Protein; Play; Process; Proteins; RNA Splicing; Relative (related person); Role; Testing; Therapeutic; Transcriptional Regulation; Viral; Viral Proteins; Virus Diseases; antiretroviral therapy; base; cofactor; design; insight; mRNA Expression; novel; novel strategies; novel therapeutics; prevent; small hairpin RNA

DESCRIPTION (provided by applicant): The HIV-1 pre-integration complex (PIC) that comprises of HIV-1 full-length DNA, viral proteins, and host proteins is essential for viral integration and replication. Previous studies have identified and characterized several human proteins that interact with HIV-1 integrase and play important roles in viral infection. However, the technical limitations in acquiring sufficient amounts of catalytically active PICs has hindered a comprehensive identification of host proteins associated with the HIV-1 PICs. We recently developed a novel approach and identified 18 new human proteins that are specifically associated with the HIV-1 PICs isolated from infected CD4+ T cells. Our preliminary study suggested that one of these proteins, non-POU domain-containing octamer-binding protein (NonO), is required for efficient HIV-1 infection in CD4+ T cells. However, it is unclear whether the other 17 PIC- associated host proteins that we identified can affect HIV-1 infection. NonO is a multifunctional nuclear protein involved in transcription regulation, mRNA splicing, and DNA repair in the cell, but the mechanism by which NonO affects HIV-1 infection is not known. We seek to address these two significant questions in this R21 proposal. We hypothesize that host proteins (such as NonO) specifically associated with catalytically active PICs in HIV-1-infected cells play a role in viral integration and infection. The following two specific aims are designed o test this hypothesis: Aim 1. To determine the role of novel PIC-associated host proteins in HIV-1 infection. In addition to NonO, we may identify other PIC-associated host proteins among these 18 candidates that can significantly affect HIV-1 infection in Aim 1. We will select 2-3 protein candidates that have the most significant effect on viral infection to further study their mechanisms of action. Aim 2. To investigate the mechanisms by which PIC-associated host proteins affect HIV-1 infection. We will first investigate the mechanism by which NonO affects HIV-1 infection, and we will then perform similar studies to examine other protein candidates identified in Aim 1. The long-term goal of this project is to understand the function and mechanism of PIC-associated host proteins in HIV-1 integration or infection and to develop novel therapeutic strategies. An emerging anti-HIV therapeutic strategy is to block the interactions between HIV-1 integrase and its critical cellular cofactors. Our proposed study has the potential to identify novel drug targets to block HIV-1 integration and infection.

描述（由申请人提供）：HIV-1预整合复合体（PIC）由HIV-1全长DNA、病毒蛋白和宿主蛋白组成，对病毒整合和复制至关重要。先前的研究已经确定并描述了几种与HIV-1整合酶相互作用并在病毒感染中发挥重要作用的人类蛋白质。然而，在获得足够数量的催化活性PICs方面的技术限制阻碍了

项目成果

SAMHD1 knockout mice: modeling retrovirus restriction in vivo.

SAMHD1 敲除小鼠：体内逆转录病毒限制模型。

• DOI: 10.1186/1742-4690-10-142
• 发表时间: 2013
• 期刊: Retrovirology
• 影响因子: 3.3
• 作者: Wu,Li