The HIV-1 virus can neutralize cellular defenses with its “viral infectivity factor (Vif).” Okinawa Institute of Science and Technology (OIST) researchers, Matthias Wolf and Takahide Kouno together with an international team of colleagues have now determined the atomic structure of the “APOBEC3G-Vif complex” using cryo-electron microscopy.

The findings are published in Nature Communications in an article titled, “Structural insights into RNA bridging between HIV-1 Vif and antiviral factor APOBEC3G.”

“Great effort has been devoted to discovering the basis of A3G-Vif interaction, the key event of HIV’s counteraction mechanism to evade antiviral innate immune response,” wrote the researchers. “Here we show reconstitution of the A3G-Vif complex and subsequent A3G ubiquitination in vitro and report the cryo-EM structure of the A3G-Vif complex at 2.8 Å resolution using solubility-enhanced variants of A3G and Vif.”

“APOBEC3G (A3G) is a key component of the human innate immune system to defend against invading viruses, getting a ride inside budding virions like in a Trojan horse so that it can modify and disable viral DNA after reverse transcription in infected cells,” explained Wolf, the senior author of the study and who leads the OIST Molecular Cryo-Electron Microscopy Unit. “But HIV-1 has evolved a counteraction mechanism in the form of its Vif protein, which inhibits this process by binding to and degrading A3G, leading to successful amplification of infectious viral particles.”

Their study is the first demonstration that this complex formation is mediated by specific RNA sequences, even though single-stranded DNA is the substrate of degradation by A3G. Their protein construct was optimized for higher solubility and could replicate the degradation pathway by A3G ubiquitination (a process that involves the transfer of ubiquitin polyubiqitination to a target protein and is important in many physiological functions) in vitro.

Their findings suggest that A3G-Vif interaction is a key event of viral immune suppression to overcome host defenses, and presents a potential new target for new therapeutics against HIV-1/AIDS.

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