SIV Deltavif Reservoirs in Vivo

体内的 SIV Deltavif 储层

• 批准号: 7167836
• 负责人: Ellen Elizabeth Sparger
• 金额: $ 11.36万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7167836
• 关键词: Lentivirus; Macaca; genes; human; infection; model; mutant; proteins; tissues; virion

DESCRIPTION (provided by applicant): The simian immunodeficiency virus (SIV) animal model presents a unique and significant opportunity for assessing novel antiviral strategies for human immunodeficiency virus (HIV)/AIDS in humans. Careful elucidation of HIV accessory gene functions in vivo in an animal model will be crucial to the design and development of targeted intervention strategies useful for treatment of human immunodeficiency virus-1 (HIV-1) infection of humans. The accessory gene vif is present in genomes of all known lentiviruses, with the exception of equine infective anemia virus (EIAV), and has been shown to be required for efficient viral replication both in vivo and in vitro for multiple animal lentiviruses. Mechanisms by which Vif functions to facilitate viral infectivity for both HIV-1 and SIV have only recently been elucidated. Vif inhibits virion incorporation of a cellular cytidine deaminase, APOBEC3G, by targeting this cellular protein for proteosomal degradation. If incorporated into virions, APOBEC3G severely restricts reverse transcription of viral RNA by inducing C to U mutations in newly synthesized negative strand viral DNA. These findings based on in vitro experiments further demonstrate the requirement of Vif for efficient lentivirus replication and distinguish this viral factor as a potential target for antiviral therapies. Our recent studies indicate that rhesus macaques inoculated with a proviral SIV vif mutant exhibit strong virus-specific cellular immune responses along with low level antiviral antibody responses. Taken together, these findings imply that replication of a wf-deleted virus is persistent in the host, although at extremely low levels. Furthermore, these observations strongly support the hypothesis of the presence of a reservoir or a specific population of target cells permissive for SIV vif-negative virus infection in vivo. This proposal intends to use infection of rhesus macaques with a SIV vif deletion mutant to identify target cell populations permissive for SIV-vif infection in vivo and to examine such populations for expression of APOBEC3A-H genes, as well as APOBEC3F and APOBEC3G protein expression. Moreover, this proposal includes an in depth analysis of APOBEC3A-H expression in specific SIV/HIV target cell populations within multiple lymphoid tissues in vivo. Given the potential significance of W-APOBEC3 interactions as a target for antiviral therapies, a clear understanding of the expression of the APOBEC3 family of proteins in the host, is critical, particularly for characterizing cell populations where APOBEC3(A-H) may be low or absent and which may support HIV-1 replication in the face of Vif-targeted antiviral therapies. Accordingly, findings from these proposed experiments may have significant impact on the design and expectation of antiviral therapeutics that target Vif and Vif interactions with cellular factors (i. e., APOBEC3 family of proteins).

描述（由申请人提供）：猴免疫缺陷病毒（SIV）动物模型为评估人类免疫缺陷病毒(HIV)/艾滋病的新型抗病毒策略提供了独特而重要的机会。在动物模型中仔细阐明HIV附属基因在体内的功能，对于设计和开发治疗人类免疫缺陷病毒-1 （HIV-1）感染的靶向干预策略至关重要。辅助基因vif存在于所有已知慢病毒的基因组中，马传染性贫血病毒（EIAV）除外，并且已被证明是多种动物慢病毒体内和体外有效病毒复制所必需的。Vif促进HIV-1和SIV病毒感染的机制直到最近才被阐明。Vif抑制病毒粒子结合细胞胞苷脱氨酶APOBEC3G，通过靶向这种细胞蛋白进行蛋白体降解。如果纳入病毒粒子，APOBEC3G通过诱导新合成的负链病毒DNA中的C到U突变，严重限制病毒RNA的逆转录。这些基于体外实验的发现进一步证明了Vif对慢病毒高效复制的要求，并将这种病毒因子区分为抗病毒治疗的潜在靶点。我们最近的研究表明，恒河猴接种了SIV vif前病毒突变体，表现出强烈的病毒特异性细胞免疫反应和低水平的抗病毒抗体反应。综上所述，这些发现表明，wf缺失病毒在宿主体内的复制是持续的，尽管复制水平极低。此外，这些观察结果有力地支持了一个假设，即存在一个储存库或一个特定的靶细胞群，允许SIV病毒阴性病毒在体内感染。本研究拟利用SIV vif缺失突变体感染恒河猴，鉴定体内允许SIV-vif感染的靶细胞群体，并检测这些群体中APOBEC3A-H基因的表达，以及APOBEC3F和APOBEC3G蛋白的表达。此外，该提案还包括深入分析APOBEC3A-H在体内多种淋巴组织中特异性SIV/HIV靶细胞群中的表达。鉴于W-APOBEC3相互作用作为抗病毒治疗靶点的潜在意义，清楚地了解APOBEC3蛋白家族在宿主中的表达是至关重要的，特别是对于表征APOBEC3（a - h）可能低或缺失的细胞群，这可能支持HIV-1在面对vif靶向抗病毒治疗时的复制。因此，这些实验的发现可能会对针对Vif和Vif与细胞因子（即APOBEC3蛋白家族）相互作用的抗病毒治疗的设计和期望产生重大影响。