This project represents our continuing investigation into the mechanism of alphavirus replication and interaction with cells. Sindbis virus (SINV) is the most valuable tool for examining fundamental issues pertaining to alphavirus replication and pathogenesis on the molecular and cellular levels. However, despite great efforts by several research groups, our knowledge of these processes is far from complete. SINV nonstructural protein nsP2 is not only a component of the replicative complexes (RCs), but is also distributed in the cytoplasm outside of the RCs and is present at high concentrations in the nuclei of infected cells. We hypothesize, on the basis of our preliminary data, that SINV nsP2 plays critical roles not only in the processing of viral nonstructural proteins and synthesis of virus-specific RNAs, but also in controlling the development of the virus-induced stress response by inhibiting transcription of cellular genes. Thus, this protein is one of the viral factors critically involved in development of cytopathic effect and downregulation of the antiviral cell response during SINV replication.
Our specific aims are: 1. To identify protein complexes formed by SINV nsP2 in different cellular compartments. 2. To study biological functions of the nsP2-binding cellular proteins. 3. To identify domains and sequences in SINV nsP2 playing critical roles in virus-host cell interactions. The results of this application will provide detailed information about the interaction of SINV nsP2 with cellular proteins in different cellular compartments. We will generate new data about the functions of cellular proteins in SINV replication and elucidate the mechanism of interference of SINV replication with cellular transcription. Using a variety of approaches, we will analyze the biological significance of these data and identify the nsP2 domains and sequences that are critical in the functioning of nsP2 in virus-host cell interactions. This information will advance our understanding of SINV pathogenesis on cellular level, and it will be mostly applicable, not only to SINV, but also to other Old World alphaviruses. The identified host proteins interacting with SINV nsP2 and involved in SINV RC formation and inhibition of cellular transcription might be used as targets for the antiviral therapy. Alphaviruses is a group of widely distributed human and animal pathogens;some of them induce highly debilitating diseases and represent a serious public health treat in the US. The goal of this application is to elucidate the role of one of the viral nonstructural protein in suppression of the antiviral response. Understanding of the virus-specific mechanisms of interference with antiviral response will lead to development of new antiviral therapeutic strategies.

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-R (02))
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Repik, Patricia M
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University of Alabama Birmingham
Schools of Medicine
United States
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Akhrymuk, Ivan; Frolov, Ilya; Frolova, Elena I (2016) Both RIG-I and MDA5 detect alphavirus replication in concentration-dependent mode. Virology 487:230-41
Reynaud, Josephine M; Lulla, Valeria; Kim, Dal Young et al. (2016) The SD1 Subdomain of Venezuelan Equine Encephalitis Virus Capsid Protein Plays a Critical Role in Nucleocapsid and Particle Assembly. J Virol 90:2008-20
Atasheva, Svetlana; Kim, Dal Young; Frolova, Elena I et al. (2015) Venezuelan equine encephalitis virus variants lacking transcription inhibitory functions demonstrate highly attenuated phenotype. J Virol 89:71-82
Reynaud, Josephine M; Kim, Dal Young; Atasheva, Svetlana et al. (2015) IFIT1 Differentially Interferes with Translation and Replication of Alphavirus Genomes and Promotes Induction of Type I Interferon. PLoS Pathog 11:e1004863
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
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
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
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

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