A synthetic lethal interaction with a viral-induced hypomorph of GBF1

Abstract Viruses co-opt host proteins to carry out replication of the virus. Host proteins thus repurposed may become functionally compromised, a situation analogous to a loss-of-function allele, which we term a viral-induced hypomorph. Tumor-specific loss-of-function alleles have successfully been targeted with drugs perturbing proteins encoded by the synthetic lethal partners of these cancer-specific mutations. Synthetic lethal interactions with viral-induced hypomorphs have yet to be demonstrated, an important first step in the development of antiviral therapeutic strategies based on the principle of synthetic lethality. We focused on Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1), a proviral host factor for many RNA viruses. A chemogenomic screen using the GBF1-specific inhibitor, golgicide A, identified 57 putative synthetic lethal partners of GBF1, including ADP-ribosylation factor 1 (ARF1). Using a poliovirus protein, 3A, to induce a GBF1-hypomorph, we observed synthetic lethality in the context of a shRNA-mediated knockdown of ARF1. These results provide a proof-of-concept that virus-induced hypomorphs are sensitive to perturbation by synthetic lethal interaction and open up a new avenue for antiviral therapeutic development.