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 BmRNA-editing enzyme catalytic-polypeptides 3) family. In the absence of Vif, these APOBEC3 proteinsare 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-box2, 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 reduceHIV-1 loads in vivo. Therefore, a major objective of this project is to determine the architecture of theVif/EloBC/Cul5/Rbx2 complex and subcomplexes with A3G
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