Variola virus, the causative agent of
smallpox, encodes approximately 200
proteins. Over 80 of these
proteins are located in the terminal regions of the genome, where
proteins associated with host immune evasion are encoded. To date, only two
variola proteins have been characterized. Both are located in the terminal regions and demonstrate immunoregulatory functions. One
protein, the
smallpox inhibitor of
complement enzymes (SPICE), is homologous to a vaccinia virus
virulence factor, the
vaccinia virus complement-control protein (VCP), which has been found experimentally to be expressed early in the course of
vaccinia infection. Both SPICE and VCP are similar in structure and function to the family of mammalian
complement regulatory
proteins, which function to prevent inadvertent injury to adjacent cells and tissues during complement activation. The second
variola protein is the variola virus high-affinity secreted
chemokine-
binding protein type II (CKBP-II, CBP-II, vCCI), which binds
CC-chemokine receptors. The
vaccinia homologue of CKBP-II is secreted both early and late in
infection. CKBP-II
proteins are highly conserved among orthopoxviruses, sharing approximately 85% homology, but are absent in eukaryotes. This characteristic sets it apart from other known
virulence factors in orthopoxviruses, which share sequence homology with known mammalian immune regulatory gene products. Future studies of additional
variola proteins may help illuminate factors associated with its virulence, pathogenesis and strict human tropism. In addition, these studies may also assist in the development of targeted
therapies for the treatment of both
smallpox and human immune-related diseases.