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）：猿类免疫缺陷病毒（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且重要的机会。仔细阐明动物模型体内 HIV 辅助基因的功能对于设计和开发可用于治疗人类免疫缺陷病毒 1 (HIV-1) 感染的针对性干预策略至关重要。辅助基因 vif 存在于除马传染性贫血病毒 (EIAV) 之外的所有已知慢病毒的基因组中，并且已被证明是多种动物慢病毒在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 通过靶向细胞蛋白进行蛋白体降解来抑制病毒颗粒掺入细胞胞苷脱氨酶 APOBEC3G。如果掺入病毒体中，APOBEC3G 通过在新合成的负链病毒 DNA 中诱导 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 有效复制慢病毒的必要性，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，接种前病毒 SIV vif 突变体的恒河猴表现出强烈的病毒特异性细胞免疫反应以及低水平的抗病毒抗体反应。总而言之，这些发现意味着 wf 删除的病毒的复制在宿主体内持续存在，尽管水平极低。此外，这些观察结果有力地支持了体内存在允许 SIV vif 阴性病毒感染的储存库或特定靶细胞群的假设。该提案旨在利用 SIV vif 缺失突变体感染恒河猴来识别体内允许 SIV-vif 感染的靶细胞群，并检查这些细胞群的 APOBEC3A-H 基因表达以及 APOBEC3F 和 APOBEC3G 蛋白表达。此外，该提案还包括对体内多个淋巴组织内特定 SIV/HIV 靶细胞群中 APOBEC3A-H 表达的深入分析。鉴于 W-APOBEC3 相互作用作为抗病毒治疗靶标的潜在重要性，清楚了解 APOBEC3 蛋白家族在宿主中的表达至关重要，特别是对于表征 APOBEC3(A-H) 可能较低或缺失的细胞群面对 Vif 靶向抗病毒疗法，这可能支持 HIV-1 复制。因此，这些拟议实验的结果可能对针对 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预期产生重大影响。