doubtedly remain to be identified. Thus, the expressed variola proteins collectively represent an untapped resource of experimental probes with which it may be possible to identify and characterize new and potentially still-unknown human immune system components.

Second, purified variola proteins might be used as potential drugs to treat human diseases. A number of poxvirus proteins that function to inhibit immune pathways in the context of viral infection also inhibit the same immune molecules when purified and tested in the absence of virus. The discovery and analysis of the biological properties of poxvirus-encoded serpins have yielded a wealth of knowledge about how viruses can modulate inflammation [54]. For example, a secreted serine proteinase inhibitor from a rabbit-specific poxvirus and a similar but different orthopoxvirus homologue of the rabbit-specific poxvirus inhibit human proteinases in vitro [55, 56]. Rabbit poxvirus proteins can prevent inflammatory cell-dependent atherosclerosis in an animal model of vascular restenosis [57]. Similarly, a variety of viral apoptosis, or programmed cell death, inhibitors, such as crmA of cowpox, offer novel avenues for approaching the therapy of diseases associated with excessive cell death [58]. A homologue gene of serp2 found in the rabbit-specific myoxoma poxvirus inhibits some of the molecules involved in controlling apoptosis, but cannot substitute for crmA [59]. Such examples suggest that some viral proteins may be uniquely specific in function. Finally, selected viral proteins from variola could perhaps stimulate immune tolerance pathways, which could lead to improved methods for blocking transplant rejection or achieving increased effectiveness of gene therapy vectors [60].

Although the above uses remain hypothetical, the opportunity to investigate such avenues of research in the future will be dependent on the results of the World Health Assembly vote on the future of variola virus.



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