Novel Poxvirus Virulence Factor A35R, Immune Suppression, and Improved Poxvirus-Based Vaccines Grant uri icon

abstract

  • Poxviruses are double stranded DNA viruses that infect a large range of hosts, including insects, reptiles, birds and mammals. The most notorious member of the Poxviridae, variola virus causing smallpox, has been eliminated from nature by vaccination programs, but it remains a bioterrorism/biowarfare threat. In addition, there are wild poxvirus populations that continue to threaten human populations. Monkeypox has infected humans in Africa and North America during the past decade and often caused significant mortality, depending on the strain. Cantagalo virus (similar to vaccinia, the smallpox vaccine) has recently been diagnosed as causing skin infections in South America. Molluscum contagiousum causes skin lesions that can last for many months in children and in immunocompromised patients. These poxvirus threats are especially of concern because of the paucity of approved therapeutics, and there is currently no publicly available poxvirus vaccine because of safety concerns. I have studied poxvirus virulence factors since 1992 and have discovered a new poxvirus virulence gene (A35R). The gene sequence is conserved in all 96 of the mammalian-tropic poxviruses sequenced thus far, suggesting a crucial role for this protein. Deletion of this gene does not affect viral replication in tissue culture cells, but the virus deletion mutant is attenuated in a mouse intranasal challenge model since the A35R gene blocks the beginning steps of the immune response in tissue culture, we hypothesize that removing this gene from poxvirus vaccines will increase the immune response to the vaccines, increasing immunogenicity and making a better vaccine. This will be directly tested in a mouse vaccine/challenge model using both replication competent and defective virus vaccines. Protective efficacy and Band T lymphocyte immune responses will be assessed. This information has important implications for poxvirus virulence, and drug and vaccine design.

date/time interval

  • August 2007 - January 2009