Innate cellular defenses of APOBEC3 cytidine deaminases and viral counter-defenses

Abstract

The APOBEC3 cytidine deaminases, which are unique to mammals, have been identified as potent innate cellular defenses against both endogenous retroelements and diverse retroviruses. To evade such host defenses, retroviruses have developed multiple strategies. This article reviews several proposed mechanisms of these viral counter-defenses. Primate lentiviruses encode a virion-infectivity factor that induces targeted destruction of APOBEC3 proteins by hijacking the cellular ubiquitin-proteasome pathway. Virion-infectivity factor molecules of HIV-1 and SIV are newly identified substrate receptor proteins that assemble with Cul5, ElonginB, ElonginC, and Rbx1 to form an E3 ubiquitin ligase and target selected APOBEC3 proteins for polyubiquitination. Foamy viruses use a different viral protein, BET, which binds and sequesters APOBEC3 away from the assembling virions. Simple retroviruses such as murine leukemia virus may avoid virion packaging of cognate APOBEC3 protein through yet another novel mechanism, in the absence of a viral regulatory factor. APOBEC3 cytidine deaminases target broad retroelements. Contemporary retroviruses have developed multiple unique strategies to combat this powerful host defense system. As a result, these retroviruses and APOBEC3 proteins maintain an equilibrium that allows regulated viral replication. These viral counter-defenses thus represent vulnerable targets for the design of new classes of antiviral inhibitors.