Parvovirus non-structural promoter P4 in host-range determination

Davis and Tattersall, BSF 2007246 Abstract The protoparvoviruses, including Minute Virus of Mice (MVM), jump the species barrier to preferentially infect and kill human cancer cells and are being actively pursued for cancer therapy. MVM infection depends on activation of the viral P4 promoter by the host cell transcription factor milieu. Since this varies from one cell type to another, we hypothesized that the P4 promoter is a host cell-type range determinant. Given current attempts to use these viruses in cancer therapy, the hypothesis has applicable as well as theoretical interest.

We tested this hypothesis by combining the labs’ expertise in virology (Tattersall) and embryonic development (Davis). Specifically, wildtype and engineered P4 promoter variant viruses were made. These were then injected into mouse embryo in utero and infection parameters measured over a 96 hour incubation. We showed that deletion of the P4 CRE element drastically decreased infection without altering host cell type. The CRE element is required in all cell types productively infected by the virus. We swapped elements of the MVM P4 promoter with those from H1. The exchange altered the host range of the virus in utero, eliminating infection in cell types infected by both MVMp and H1. The chimeric virus did pick up an additional host cell type infected by H1, but not MVMp - fat cells. The data show that alterations of the MVMp P4 promoter can shift the virus host range without drastic reduction in cell-type specific infection. The P4 promoter of MVM is host range determinant.