Bovine herpesvirus type 1 as a novel oncolytic virus

Abstract

Oncolytic virotherapy is a promising avenue of cancer gene therapy. Current vectors include human viruses that have been engineered to replicate in tumor cells or nonhuman viruses that are naturally oncotropic and preferentially replicate in tumor cells harboring defects in innate immune pathways such as the type 1 interferon (IFN) pathway. Bovine herpesvirus type 1 (BHV-1) is a species-specific herpesvirus closely related to the human herpes simplex virus type 1 (HSV-1). Although BHV-1 does not efficiently replicate in and affect cellular viability of normal human cells, it is capable of infecting and killing various immortalized and transformed human cell types. Surprisingly, BHV-1 infection of human cells fails to elicit IFN production at the mRNA or protein level and the ability of BHV-1 to kill immortalized and transformed human cells does not correlate with defects in IFN pathways. Furthermore, although some cross-reactivity between BHV-1 and HSV-1 exists, the majority of human antibody or serum samples tested failed to neutralize BHV-1 despite possessing HSV-1 neutralizing capacity. Thus, BHV-1 is a novel candidate oncolytic virus with a distinct mechanism of tumor targeting.

Permissiveness of Human Cancer Cells to Oncolytic Bovine Herpesvirus 1 Is Mediated in Part by KRAS Activity

“…Data from our group indicate that BHV-1 oncolysis does not correlate with defects in type I IFN signaling (22). Furthermore, BHV-1 is able to distinguish between normal and immortalized cell types (22), suggesting that immortalization and cellular changes occurring during this process may confer sensitivity to BHV-1. However, mutations in TP53 and retinoblastoma (RB1) protein, which are commonly deregulated during immortalization, do not correlate with permissivity to BHV-1 (Fig.…”

“…To fully appreciate the oncolytic capacity of BHV-1, particularly in light of its unique properties (22,23), we screened the NCI panel of 59 established human tumor cell lines, comparing BHV-1 to our prototypic HSV-1 vector KM100. The capacities of BHV-1 and KM100 to initiate replication in and decrease the viability of the NCI panel were assessed.…”

“…Genes expressed by BHV-1 are generally named after the coinciding HSV-1 genes, which often have similar functions (8,20,21). While BHV-1 is unable to productively infect normal human cells (14,22), human immortalized, transformed, and breast cancer-initiating cells are permissive to infection (22,23). Interestingly, the ability of BHV-1 to kill human breast tumor cells and breast cancer-initiating cells is not contingent upon virus replication or the production of a viral burst (23).…”

“…Interestingly, the ability of BHV-1 to kill human breast tumor cells and breast cancer-initiating cells is not contingent upon virus replication or the production of a viral burst (23). Furthermore, in contrast to other species-specific viruses, sensitivity to BHV-1 does not correlate with type I IFN signaling (22). Thus, the determinants of permissivity for BHV-1 in human cells are unknown.…”

Herpes Simplex Type 1 for Use in Cancer Gene Therapy: Looking Backward to Move Forward

“…Also, cattle farmers whom are routinely exposed to the virus do not seroconvert. Rodrigues et al (2010) showed that human transformed and phenotypically normal immortalized cell types are permissive to BHV-1, while normal primary cell types are relatively resistant to BHV-1 infection (Figure 2). BHV-1 induces cytopathic effects (CPE) and decreases cellular metabolism in immortalized and transformed cells from the lung, mammary, bone and prostate origins with varying efficiency.…”