Poxvirus interferon-resistance genes: Their evolutionary past and role in anti-cancer therapy

The poxvirus E3L and K3L genes function as interferon (IFN)-resistance genes. This investigation examines their evolutionary past as well as their role in viral oncolysis. An evolutionary analysis demonstrates that these genes are highly conserved amongst the orthopoxviruses, with homologs present in the capripoxviruses, leporipoxviruses, suipoxviruses, and yatapoxviruses. E3L is present in the parapoxviruses but K3L is absent. Neither gene, however, is present in the avipoxviruses nor the molluscipoxviruses. Results from this study support a model for poxviral evolution that states avipoxviruses diverged at an early point in history. After this split, ancient parapoxviruses obtained an E3L-like sequence during a cellular capture event while molluscipoxviruses did not. A second capture event of a K3L-like protein resulted in parapoxviruses diverging from the remaining chordopoxviruses. Some lineages of chordopoxviruses have undergone partial deletions or point mutations of the E3L and K3L genes to form the modern group of E3L and K3L genes. These mutations suggest a varied necessity for the IFN-resistance genes likely altering pathogenesis or host-range.; Vaccinia virus (VV), a member of the orthopox genus, is known for its role as a smallpox vaccine. By creating mutations in VVE3L, we have developed several oncolytic viruses that preferentially replicate in and lyse ras-transformed cells. The mutant VVs constructed are PKR-sensitive and are thus dependent on the Ras-induced PKR inhibitor present in cells with an overactive Ras pathway or other IFN system dysregulation. When one of two tumors was treated, mutant VV induced regression of both local and distant breast cancer xenografts in SCID/bg mice. The anti-cancer regimen was not toxic, causing no significant weight loss or pathogenesis in treated mice. Given the recombination properties of VV and the varied genes encoded by VV that affect cell division and PKR activation, this system offers the potential of multiple therapeutic vectors. Targeted therapy, such as the PKR/IFN sensitive and ras-dependent VV, may be part of the future of individualized treatment for cancer patients.