Restriction/Degradation (Vif)

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Vif Projects Co-Leaders:  John Gross, Charles Craik, Nevan Krogan

Restriction factors are a branch of the innate immune system that potently inhibit viral replication. A number of viral pathogens encode accessory proteins that can antagonize restriction factors, which allows viral dissemination in host.  Over evolutionary time, restriction factors evolve to escape viral antagonists, limiting the host range of viruses. In turn, viruses can adapt to these changes and cross species into new hosts by rapid evolution of accessory proteins. The primate APOBEC3 cytidine deaminases are arguably the most extensively studied family of restriction factors. They block the spread of retroviruses and retroelements by hypermutating their genomes and have the potential to inhibit the AIDS virus, HIV-1. Vif antagonizes A3 family members targeting them to the 26S proteasome by hijacking the cellular ubiquitin E3 ligase CRL5 (CUL5/RBX2/ELOBC) and the transcription cofactor Core Binding Factor Beta (CBFβ. To help understand the structural basis for how Vif counteracts this essential host defense, this project combines the precision and specificity of structural biology and quantitative biochemistry with the power and flexibility of complementary approaches, including cross-linking mass spectrometry (XL-MS) and integrative modeling. We will also use Fab-assisted cryo-EM to determine atomic resolution structures of A3G and Vif-A3G complexes.

Prior studies indicate Vif downregulates CBFβdependent genes in CD4+ T-cells, which includes restrictive A3 family members, yet the mechanism of how this is achieved is not understood. The capacity of Vif to reduce A3 transcription through hijacking CBFβmay have allowed primate lentiviruses to counteract an extended A3 repertoire. This project will employ systematic and unbiased studies to provide deeper insights into the degree to which Vif depends on host factors and uses them to perturb host innate immunity to promote infection.