This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The terrorist events of 2001 have led us to question our current health guidelines and to re-evaluate the advantages and disadvantages of reinitiating wide-scale small pox vaccination. However, vaccination with the current vaccinia (VV) vaccine preparation is associated with significant side effects, including disseminated VV infection that can lead to permanent disfiguration or mortality. A recent model describing the morbidity and mortality associated with mass vaccination suggests that 190 to 285 deaths will likely occur due to vaccination alone--even under conditions in which only 75% of the population is vaccinated and highly susceptible populates are excluded. Particularly devastating effects are expected to occur in immunocompromised individuals, who have yet to be determined to have been infected with the human immunodeficiency virus (HIV). Thus, new vaccine and therapeutic approaches are needed to combat the potential use of poxviruses as bioterrorism agents, and to protect individuals from the potential complications associated with the current vaccine. Unfortunately, the mechanisms of immune protection against smallpox or the pathogenesis of small-pox like diseases have not all been defined, and only limited drug target discovery efforts exist. The only animal model that recapitulates all aspects of smallpox is the infection of nonhuman primates (NHP) with monkeypox virus (MPV), an orthopox virus that is genetically similar to smallpox and also infects humans and induces disease that is indistinguishable from smallpox. Thus, we propose to investigate whether specific cellular processes required for poxvirus production are suitable targets in vivo to inhibit MPV sequeale and if inhibition of these processes can still induce protective immune responses. Our preliminary in vitro studies indicate that preventing actin polymerization with Abl-family tyrosine kinase inhibitors is effective at eliminating spread of virus in cell culture.
Specific Aim 1 : To define the ability of signal transduction inhibitor number 571 (STI-571 or Gleevec) to inhibit MPV-disease in experimentally infected rhesus macaques (RM) given lethal dose of MPV.
Specific Aim 2 : To determine the immunological consequence of early intervention with STI-571.
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