In Part I of its report, the committee illustrates the complex structure, genome, and replication cycle of poxviruses (in particular of orthopoxviruses). Several enzymes made by orthopoxviruses are possible targets for antiviral drugs, among them several important in viral replication. The ideal viral enzyme target would be structurally and mechanistically peculiar to poxviruses. In this regard, the enzymes listed in Table 3 of the full report are promising candidates. Of those enzymes, the atomic structures of only two, the topoisomerase 1 and the poly(A) polymerase stimulatory subunit, have been thus far determined.
The committee goes on to describe six subjects of poxvirus research particularly ripe for investigation. These include:
the mechanism of entry into host cells;
compartmentalization and intracellular organization of replication, transcription, and translation;
viral manipulation of host-cell membrane traffic;
viral subversion and exploitation of host-cell signaling pathways;
viral exploitation of motor proteins for movement within a cell and for propulsion toward another cell; and,
mechanisms of host-range restriction in vitro and in vivo.
These subjects overlap, but the list gives some indication of the array of specialized biological expertise that could be brought to bear on poxvirus biology in order to expand our understanding of the infectious process and lead to novel antiviral strategies.
Another research focus that could yield therapeutically important information is the study of the viral and cellular determinants of the host response. As is the case with many other viruses, little is known with certainty about the molecular details of protective immunity against variola viruses or other poxviruses. Consequently, research is needed on all aspects of the innate and acquired immune response. This research requires that animal models be further developed--another area in need of study. The study of the immune response to variola virus could also be enhanced by greater knowledge of the variola proteome. Because only the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia and the Vektor Institute in Novosibirsk, Russia are permitted to work with the virus and its complete genome, a coordinated international effort of those two centers with other groups working on smaller parts of the genome would be an important contribution to the field.
In the committee’s view, the poxviruses offer a rich opportunity for investigation, and developing an antiviral drug against smallpox is an achievable goal. The challenge is to expedite that development by mobilizing scientific expertise in the academic and industrial research communities, and coordinating their efforts with the roles played by federal agencies involved in poxvirus research, including the National Institutes of Health (NIH), the US Army Medical Research Institute on Infectious Disease (USAMRIID), the Centers for Disease Control and Prevention (CDC), and the Food and Drug Administration (FDA)—the latter having the ultimate authority to approve a drug for use.