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Pathogenicity of bovine viral diarrhea virus is associated with production of the NS3 protein. Two cytopathic viruses, Osloss and CP1, in which the ubiquitin sequence (UCH) has been inserted at different sites, are shown. In Osloss, UCH has been inserted into the NS2-3 precursor, and NS3 is produced. In CP1, a duplication has also occurred such that an additional copy of NS3 is present after the UCH sequence.

A remarkable property of pestiviruses, members of the Flaviviridae, is that RNA recombination generates viruses that cause disease. Bovine viral diarrhea virus causes a usually fatal gastrointestinal disease. Infection of a fetus with this virus during the first trimester is noncytopathic, but RNA recombination produces a cytopathic virus that causes severe gastrointestinal disease after the animal is born.

Pathogenicity of bovine viral diarrhea virus is associated with the synthesis of a nonstructural protein, NS3, encoded by the recombinant cytopathic virus (see the figure). The NS3 protein cannot be made in cells infected by the noncytopathic parental virus because its precursor, the NS2-3 protein, is not proteolytically processed. In contrast, NS3 is synthesized in cells infected by the cytopathic virus because RNA recombination adds an extra protease cleavage site in the viral polyprotein, precisely at the N terminus of the NS3 protein (see the figure). This cleavage site can be created in several ways. One of the most frequent is insertion of a cellular RNA sequence coding for ubiquitin, which targets cellular proteins for degradation. Insertion of ubiquitin at the N terminus of NS3 permits cleavage of NS2-3 by any member of a wide-spread family of cellular proteases. This recombination event provides a selective advantage, because pathogenic viruses outgrow non-pathogenic ones. Why cytopathogenicity is associated with release of the NS3 protein, which is thought to be part of the machinery for genomic RNA replication, is not known.

Retroviruses acquire cellular genes by recombination, and the resulting viruses can have lethal disease potential (Volume II, Chapter 6).