Viral vascular endothelial growth factor plays a critical role in orf virus infection

Infection by the parapoxvirus orf virus causes proliferative skin lesions i n which extensive capillary proliferation and dilation are prominent histol ogical features. This infective phenotype may be linked to a unique virus-e ncoded factor, a distinctive new member of the vascular endothelial growth factor (VEGF) family of molecules. We constructed a recombinant orf virus i n which the VEGF-like gene was disrupted and show that inactivation of this gene resulted in the loss of three VEGF activities expressed by the parent virus: mitogenesis of vascular endothelial cells, induction of vascular pe rmeability, and activation of VEGF receptor 2. We used the recombinant orf virus to assess the contribution of the viral VEGF to the vascular response seen during orf virus infection of skin. Our results demonstrate that the viral VEGF, while recognizing a unique profile of the known VEGF receptors (receptor 2 and neuropilin 1), is able to stimulate a striking proliferatio n of blood vessels in the dermis underlying the site of infection. Furtherm ore, the data demonstrate that the viral VEGF participates in promoting a d istinctive pattern of epidermal proliferation. Loss of a functional viral V EGF resulted in lesions with markedly reduced clinical indications of infec tion. However, viral replication in the early stages of infection was not i mpaired, and only at later times did it appear that replication of the reco mbinant virus might be reduced.