Vif

项目4--VIF(Peterlin和Gros.项目负责人) 病毒感染性因子Vif是灵长类慢病毒HIV-1，HIV-2， 和SIV。如果没有VIF，这些病毒不会在非允许细胞或宿主中复制。Vif停用 细胞胞苷脱氨酶ASF和A3G是载脂蛋白B的成员 3)信使核糖核酸编辑酶催化多肽家族。在没有Vif的情况下，这些APOBEC3蛋白 被结合到新的病毒颗粒中，在那里它们在负链cdna中脱氨基 逆转录。这些DNA损伤会导致病毒DNA降解或引入有害物质 突变。此外，APOBEC3蛋白可以在没有酶的情况下抑制病毒复制 活性，可能是通过改变逆转录过程本身。因此，APOBEC蛋白保护细胞 VIF已经进化成提供一种基本的病毒对抗防御。 VIF的一个关键作用是促进泛素化和随后由 蛋白质小体。VIF招募A3G和ASF到包括cullin-5，Ring-box的细胞泛素蛋白连接酶 和Elongins B和C(EloBC)。即使是适度抑制Vif功能，也可以通过干扰结合 A3G和/或ASF，或通过阻断EloBC/Cul5/Rbx2 E3连接酶的招募，可能会显著减少 体内携带HIV-1病毒。因此，该项目的一个主要目标是确定 Vif/EloBC/Cul5/Rbx2复合体及其与A3G的亚复合体。

PROJECT 4 - Vif (PETERLIN AND GROSS. PROJECT LEADERS) The viral infectivity factor Vif is an essential accessory protein of primate lentiviruses, HIV-1, HIV-2, and SIV. Without Vif, these viruses do not replicate in non-permissive cells or in the host. Vif inactivates the cellular cytidine deaminases ASF and A3G, which are members of the APOBEC3 (apolipoprotein B mRNA-editing enzyme catalytic-polypeptides 3) family. In the absence of Vif, these APOBEC3 proteins are incorporated into new viral particles where they deaminate cytidines in the minus-strand cDNA during reverse transcription. These DNA lesions result in viral DNA degradation or introduction of deleterious mutations. In addition, the APOBEC3 proteins can inhibit viral replication in the absence of their enzymatic activity, possibly by altering the reverse transcription process itself. Thus, APOBEC proteins protect cells against HIV, and Vif has evolved to provide an essential viral counter defense. A key role for Vif is to promote ubiquitination and subsequent destruction of A3G and ASF by the proteosome. Vif recruits A3G and ASF to a cellular ubiquitin protein ligase that includes Cullin-5, Ring-box 2, and Elongins B and C (EloBC). Even modest inhibition of Vif function, either by interfering with binding to A3G and/or ASF or by blocking recruitment of the EloBC/Cul5/Rbx2 E3 ligase, might significantly reduce HIV-1 loads in vivo. Therefore, a major objective of this project is to determine the architecture of the Vif/EloBC/Cul5/Rbx2 complex and subcomplexes with A3G.