The Alphavirus genus in the Togaviridae family includes a number of important human and animal pathogens, including Venezuelan (VEEV), eastern (EEEV) and western equine encephalitis (WEEV) viruses. The latter constitute a serious public health threat in the US, because they continuously circulate in nature and have the ability to cause fatal disease in humans and horses. In addition, EEEV, WEEV and, in particular, VEEV have the potential for use by terrorists and as biological warfare agents. In spite of the continuous threat of VEEV epidemics, the biology of VEEV, in particular the molecular basis of its high virulence, has been studied less intensively than that of other alphaviruses. It was believed that Sindbis (SINV) and Semliki Forest (SFV) viruses, which are dramatically less pathogenic than VEEV, represent good models for studying the mechanism of VEEV replication and virus-host interactions. However, results from recent comparative studies with VEEV and SINV suggested that VEEV replication and its pathogenesis strongly differ from those previously described for SINV. Hence, a great part of our knowledge about SINV biology cannot be directly applied to VEEV. Our preliminary studies strongly suggested that the VEEV capsid plays critical roles in inhibiting both nucleocytoplasmic trafficking and cellular transcription and, thus, downregulation of the innate immune response. Our results also suggested the 5'UTR of the VEEV genome is one of the important determinants of viral pathogenesis. Therefore, the proposed research is aimed at further understanding the functions of VEEV capsid and 5'UTR in virus replication, and in determining virus pathogenesis at different levels. The proposed experiments are organized into three aims.
In specific aim 1, we intend to define functioning of VEEV capsid in the nucleocytoplasmic transport inhibition.
In specific aim 2, we will perform a detailed investigation of the effects of the strain-specific mutations in the 5'UTR sequence on VEEV replication and pathogenesis on molecular and cellular levels;and in specific aim 3, we will apply already available information and new data that will be generated in our proposed experiments to develop new, highly attenuated strains of VEEV for vaccine applications.
The specific aims represent three independent lines of research, but they are expected to generate complementary data. The results of this study will also be applicable to other encephalitogenic alphaviruses, such as EEEV and WEEV.

Public Health Relevance

Alphaviruses comprise a group of widely distributed human and animal pathogens;some of them induce highly debilitating diseases and represent a serious public health threat in the US. The goal of this application is to understand the role of viral proteins in modification of the intracellular environment during virus replication and development of new, highly attenuated, live vaccines against encephalitogenic alphaviruses.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-M (02))
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Repik, Patricia M
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University of Alabama Birmingham
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Kim, Dal Young; Atasheva, Svetlana; McAuley, Alexander J et al. (2014) Enhancement of protein expression by alphavirus replicons by designing self-replicating subgenomic RNAs. Proc Natl Acad Sci U S A 111:10708-13
Atasheva, Svetlana; Frolova, Elena I; Frolov, Ilya (2014) Interferon-stimulated poly(ADP-Ribose) polymerases are potent inhibitors of cellular translation and virus replication. J Virol 88:2116-30
Kim, Dal Young; Atasheva, Svetlana; Frolova, Elena I et al. (2013) Venezuelan equine encephalitis virus nsP2 protein regulates packaging of the viral genome into infectious virions. J Virol 87:4202-13
Lulla, Valeria; Kim, Dal Young; Frolova, Elena I et al. (2013) The amino-terminal domain of alphavirus capsid protein is dispensable for viral particle assembly but regulates RNA encapsidation through cooperative functions of its subdomains. J Virol 87:12003-19
Atasheva, Svetlana; Kim, Dal Young; Akhrymuk, Maryna et al. (2013) Pseudoinfectious Venezuelan equine encephalitis virus: a new means of alphavirus attenuation. J Virol 87:2023-35
Foy, Niall J; Akhrymuk, Maryna; Shustov, Alexander V et al. (2013) Hypervariable domain of nonstructural protein nsP3 of Venezuelan equine encephalitis virus determines cell-specific mode of virus replication. J Virol 87:7569-84
Foy, Niall J; Akhrymuk, Maryna; Akhrymuk, Ivan et al. (2013) Hypervariable domains of nsP3 proteins of New World and Old World alphaviruses mediate formation of distinct, virus-specific protein complexes. J Virol 87:1997-2010
Frolov, Ilya; Akhrymuk, Maryna; Akhrymuk, Ivan et al. (2012) Early events in alphavirus replication determine the outcome of infection. J Virol 86:5055-66
Kim, Dal Young; Firth, Andrew E; Atasheva, Svetlana et al. (2011) Conservation of a packaging signal and the viral genome RNA packaging mechanism in alphavirus evolution. J Virol 85:8022-36
Kim, Dal Young; Atasheva, Svetlana; Foy, Niall J et al. (2011) Design of chimeric alphaviruses with a programmed, attenuated, cell type-restricted phenotype. J Virol 85:4363-76

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