Interdisciplinary Training

Molly Orton

"Host vs. Virus: Genetic Conflict Between Evolving Antiviral Host Genes and their Antagonistic Viral Counterparts"

Immunodeficiency viruses endemically infect many African primates. It is not well understood what barriers restrict cross-species transmission, particularly from monkeys to humans, and the relative likelihood that such transmission events will occur given a particular viral strain. One such barrier to transmission is APOBEC3G, a host restriction factor that evolved millions of years before lentiviruses invaded the primate lineage and protects cells from infection through mutation of the viral genome. The success of lentiviruses in counteracting the lethal effects of APOBEC3G is dependent on a virally-encoded factor, Virion Infectivity Factor (vif), that binds APOBEC3G and targets it for degradation. Vif, despite its conserved function, is highly divergent among viral variants. We hypothesize that vif is in direct genetic conflict with APOBEC3G, driving rapid change in this viral factor. We will test the hypothesis that vif's rapid evolution allows for stable transmission of the virus from one species to another despite the presence of species-specific APOBEC3G variants. Through phylogenetic analysis we will reconstruct the hypothetical ancestral sequences of both vif and APOBEC3G, allowing us to test the specificity of the Vif/APOBEC3G interaction throughout evolution. We will also use directed evolution to evolve Vif proteins in vitro to define the barriers to APOBEC3G-dependent inter-species transmission. Finally, we will analyze the selective pressures acting on Vif throughout its evolution to identify domains and residues that are either important for function or are in direct genetic conflict with a host protein, such as APOBEC3G.

Fred Hutchinson Cancer Research Center is a world leader in research to prevent, detect and treat cancer and other life-threatening diseases.