The Role of Vpr and Vpx in Lentivirus Replication

Vpr和Vpx在慢病毒复制中的作用

基本信息

批准号：
9296016
负责人：
Nathaniel R. Landau
金额：
$ 42.38万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-15 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9296016
关键词：
Address Amino Acid Sequence Amino Acids Antiviral Agents Binding Biochemical Biological Assay Cell Cycle Cell Nucleus Cell physiology Cells Co-Immunoprecipitations Collaborations Coupled DNA Dendritic Cells Drops Effectiveness Engineering Enzymes Exonuclease Flow Cytometry Funding Goals HIV HIV-1 HIV-2 Human Immune response Immune system Infection Innate Immune Response Innate Immune System Integration Host Factors Laboratories Leukocytes Light Location Lymphoid Mass Spectrum Analysis Medical Medical center Modeling Mus Mutate Myeloid Cells Natural Immunity Nucleotides Pathogenesis Pathogenicity Phosphodiesterase I Phosphoric Monoester Hydrolases Play Population Post Translational Modification Analysis Post-Translational Protein Processing Property Proteins Proteomics Recombinants Regulation Research Reverse Transcription Role Sampling Subfamily lentivirinae System Testing Tetracyclines Therapeutic United States National Institutes of Health Universities Viral Genome Virion Virus Virus Replication base biobank cellular targeting clinical material experience fighting genetic regulatory protein immune activation in vitro Assay in vivo inducible gene expression infectious disease treatment inorganic phosphate insight macrophage monocyte mutant nonhuman primate nuclease pathogen prevent public health relevance transmission process tripolyphosphate ubiquitin ligase ubiquitin-protein ligase vpr Gene Products

项目摘要

DESCRIPTION (provided by applicant): HIV-1 and other lentiviruses encode accessory proteins, each of which plays a role in facilitating virus replication and causing pathogenesis. Several of the accessory proteins exert their effect by counteracting antiviral cell proteins. This project focuses on understanding how the two HIV-related accessory proteins, Vpr and Vpx, facilitate virus replication. These proteins are 50% similar in amino acid sequence, are packaged in the virion, localize to the nucleus and bind a specific E3 ubiquitin ligase. Vpx, which is encoded in HIV-2 and SIVmac but not HIV-1, targets the cellular enzyme SAMHD1 for degradation. The target of Vpr has not yet been identified. The mechanism by which SAMHD1 inhibits viruses is not clear. It is a phosphohydrolase that when expressed in myeloid cells, removes the phosphates from the deoxynucleotide triphosphates, depleting the pool of intracellular dNTPs. SAMHD1 is also an exonuclease and which of these activities restricts virus replication is not clear. SAMHD1 does not block the replication of SIVmac or HIV-2 as these viruses encode Vpx. This project seeks to understand (i) the mechanism by which SAMHD1 restricts HIV-1; (ii) how Vpx binds and targets SAMHD1 for degradation; (iii) how Vpx is released from the virus following infection; (iv) how the enzymatic activity of the protein is regulated by post-translational modifications or by associating with regulatory proteins; (v) which amino acid residues of Vpx and SAMHD1 allow the proteins to interact; (vi) how Vpx is imported into the nucleus and (vii) the role of SAMHD1 in the innate immune response to HIV-1 infection. Lastly, an inducible expression system for Vpr will be established to identify the targeted host factor. The findings will shed light on a new mechanism by which the innate immune system restricts HIV-1 and other human pathogens and how viruses have evolved to escape the restriction. Understanding this may provide strategies to therapeutically enhance the effectiveness of the innate immune response for the treatment of infectious diseases.

描述（由申请人提供）：HIV-1和其他慢病毒编码辅助蛋白，每种蛋白质都在促进病毒复制和引起发病机理中起作用。几种辅助蛋白通过抵消抗病毒细胞蛋白来发挥其作用。这项目着重于了解两种与HIV相关的辅助蛋白（VPR和VPX）如何促进病毒复制。这些蛋白质在氨基酸序列中的50％相似，在病毒粒子中包装，定位于细胞核并结合特定的E3泛素连接酶。 VPX，哪个在HIV-2和SIVMAC中编码，而不是HIV-1，靶向细胞酶SAMHD1以降解。 VPR的目标尚未确定。 SAMHD1抑制病毒的机制尚不清楚。这是一种磷酸化水酶，当在髓样细胞中表达时，从脱氧核苷酸三磷酸盐中去除磷酸盐，从而耗尽细胞内DNTP的池。 SAMHD1也是一种核酸酶，其中哪些活动限制了病毒复制，尚不清楚。 SAMHD1不会阻止SIVMAC或HIV-2的复制，因为这些病毒编码VPX。该项目试图了解（i）SAMHD1限制HIV-1的机制；（ii）VPX如何结合和靶向SAMHD1进行降解；（iii）感染后如何从病毒中释放VPX；（iv）蛋白质的酶活性如何受翻译后修饰或与调节蛋白相关的调节；（v）哪个 VPX和SAMHD1的氨基酸残基允许蛋白质相互作用。（vi）如何将VPX进口到核和（vii）SAMHD1在对HIV-1感染的先天免疫反应中的作用。最后，将建立一个可诱导的VPR表达系统，以识别目标宿主因子。这些发现将阐明一种新的机制，其先天免疫系统限制了HIV-1和其他人类病原体以及病毒如何发展以逃避限制。理解这可能会提供治疗策略，以增强先天免疫反应治疗传染病的有效性。