Myxomatosis in European rabbits is a severely debilitating disease characterized by profound systemic cellular immunosuppression and a high rate of mortality. The causative agent, myxoma virus, is a member of the poxvirus family and prototype of the Leporipoxvirus genus. As a major step toward defining the genetic strategies by which the virus circumvents host antiviral responses, the genomic DNA sequence of myxoma virus, strain Lausanne, was determined. A total of 171 open reading frames were assigned to cover the 161.8-kb genome, including two copies each of the 12 genes that map within the 11.5-kb terminal inverted repeats. Database searches revealed a central core of approximately 120 kb that encodes more than 100 genes that exhibit close relationships to the conserved genes of members of other poxvirus genera. Open reading frames with predicted signal sequences, localization motifs, or homology to known proteins with immunomodulatory or host-range functions were examined more extensively for predicted features such as hydrophobic regions, nucleic acid binding domains, ankyrin repeats, serpin signatures, lectin domains. and structural cysteine spacings. As a result, several novel, potentially immunomodulatory proteins have been identified, including a family with multiple ankyrin-repeat domains, an OX-2 like member of the neural cell adhesion molecule family, a third myxoma serpin, a putative chemokine receptor fragment, two natural killer receptor-like species, and a variety of species with domains closely related to diverse host immune regulatory proteins. Coupled with the genomic sequencing of the related leporipoxvirus Shope fibroma virus, this work affirms the existence of a conserved complement of poxvirus-specific core genes and expands the growing repertoire of virus genes that confer the unique capacity of each poxvirus family member to counter the immune responses of the infected host.

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Vertebrate poxviruses encode homologs of cellular cupro-zinc superoxide dismutases (Cu-Zn SOD). In this study we have examined the molecular genetic properties of two Cu-Zn SOD homologs encoded by the Shope fibroma virus (SFV) and myxoma virus. These Leporipoxvirus proteins should be catalytically inactive as judged by the point mutations which alter a key catalytic arginine and restructure the predicted Cu-binding domain. This prediction was confirmed using in situ gel assays and recombinant proteins produced both in bacteria and in mammalian cells. Western blot analysis showed that these proteins are produced in abundance late in infection and can, upon exposure to oxidizing conditions, form disulfide cross-linked dimers. They are also virion components and not essential for growth in culture or virulence. Leporipoxvirus Cu-Zn SOD homologs affected two phenotypes. First, deletion of the myxoma M131R gene caused the mutant virus to grow better ( approximately 10-fold) in culture than does the wild-type parent. Second, expression of either native or recombinant Leporipoxvirus proteins is accompanied by a decline in cellular Cu-Zn SOD activity. We concluded that these gene products can somehow modulate the activity of host Cu-Zn SODs, but what advantage is thus gained by the virus remains to be established.

The DNA sequence of the HindIII Q2 fragment near the left terminus of the capripoxvirus (KS-1 strain) genome was determined. The sequence contains two complete open reading frames (ORFs) and a part of a third. Analysis of the deduced amino acid sequence of one of these ORFs, Q2/3L, revealed that this gene has the capacity to encode a protein which is related to members of the G-protein coupled chemokine receptor subfamily, the swinepoxvirus K2R and the human cytomegalovirus US28 ORFs. It has the key structural characteristics of the G-protein-coupled receptor superfamily, e.g., seven hydrophobic regions, predicted to span the cell membrane, and the cysteine residues in the first and second extracellular loops that are implicated in formation of a disulfide bond. Southern blot analysis showed that all three species of the Capripoxvirus genus, i.e., sheep pox, goat pox, and lumpy skin disease of cattle, contain copies of this putative G-protein-coupled chemokine receptor homologue.

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