The molecular arms race between primate APOBEC3G and lentiviral Vif

APOBEC3 family members are powerful restriction factors that dominantly block retroviral replication by hyperediting cDNA as it synthesized by reverse-transcription inside the capsid core. Primate lentiviral Vif counteracts APOBEC3 family members by targeting them for degradation by the 26S proteasome. Over millions of years of primate evolution, some APOBEC3 family members undergo diversifying selection to escape antagonism by Vif, thereby limiting the host range of primate lentiviruses. However, lentiviral Vif adapts to re-establish infection. Our lab is interested in how these molecular arms races play out at the molecular level and we combine biochemistry and structural biology with viral genetics and evolutionary analysis to better understand the physical manifestation of genetic conflicts.

Vif hijacks a ubiquitin E3 ligase to antagonize APOBEC3 family members. We have recently determined a 2.8 Angstrom resolution cryoEM structure of human APOBEC3G bound to HIV-1 Vif (Li et al, Nature, 2023). Unexpectedly, we discovered an RNA molecule acts as a molecular glue for the Vif-A3G interaction. An essential step for retroviral restriction is binding to genomic RNA for encapsidation, so that APOBEC3 can be near cDNA as it emerges from the reverse transcription complex. We hypothesize that HIV-1 Vif antagonizes APOBEC3G when bound to viral genomic RNA en route to packaging. This study shows A3G binding to Vif is not restricted to the evolutionary dynamic interface subject to diversifying selection and adaptation, contrary to popular models of molecular arms-race, but rather also includes a conserved interface through RNA binding that helps position key residues necessary for viral antagonism of a host antiviral gene. Going forward we will determine if this mode of RNA interaction is conserved in ancestral SIVvif complexes with cognate A3G and determine if cofactors such as RNA are required for antagonism of other A3 family members as part of an ongoing collaboration with Drs Michael Emerman and Yifan Cheng of the HARC Center.