The medical and agricultural importance of picornavirus-caused disease has long targeted these agents for intensive laboratory study. The family encompasses a diverse variety of pathogenic agents, such as polio, rhino, foot-and mouth-disease, hepatitis A, coxsackie, and the murine cadioviruses (among others). The small size of the RNA genome (about 8,000 bases) and the relatively simple nature of the icosametric capsid shell have allowed facile manipulation of genomes as infectious CDNA copies, and determination of several virion structures to atomic resolution. These powerful tools not withstanding, there still remain many unresolved questions about how or why a specific infection does indeed bring about a particular course of disease within its natural host. Central to these processes is the molecular examination of all facets of a virus life cycle, especially those ensuing within the infected cell. Such studies not only bring to light the (exploitable) individualities of particular viral phenotypes, but also serve as critical probes to the inner workings of elementary biological phenomena whose disruption through infection can mediate the expression of disease. This program focuses on the murine cardioviruses, encephalomyocarditis virus (EMCV) and Mengovirus. The special propensity of cardioviral RNAs facilitate efficient translation in cell-free extracts, is a hallmark of these genomes, and makes these isolates exceptionally useful experimental subjects for molecular dissection of the pico mavirus life cycle. The goals of this investigation are to explore and define the relationship of the cardiovirus genus to other members of the piconavirus family, and to exploit the unique features of cardioviruses to examine fundamental molecular questions about piconaviral translation, proteolytic processing and morphogenesis.
The specific aims are: (1) To define the sequence and structural contexts required for the novel NPGP """"""""suicide"""""""" cleavage that is responsible for primary proteolytic processing of cardioviral polyprotein; (2) To evaluate the in vivo effects of engineered mutations introduced into the viral 3C protease, its processing sites, or other relevant genomic locations, and to correlate these results with specific phases or defects in the cardioviral life cycle; (3) To probe distinctive sequence and structural elements within the 5' noncoding region of cardioviral RNAs, and assess their responsibilities in cap-independent translation initiation and in viral-induced host protein shut-off during natural infection; and (4) To compare and contrast all available piconavirus sequence data by computer analysis, with special emphasis of correlative support for a revised taxonomic ordering of the family. Innovative, computer-generated graphic displays of internal and external virion capsid surfaces will also be advanced, for detailed molecular surface maps and topographical feature comparisons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI017331-15
Application #
2060497
Study Section
Virology Study Section (VR)
Project Start
1980-12-01
Project End
1997-02-28
Budget Start
1995-03-01
Budget End
1996-02-29
Support Year
15
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Ciomperlik, Jessica J; Basta, Holly A; Palmenberg, Ann C (2016) Cardiovirus Leader proteins bind exportins: Implications for virus replication and nucleocytoplasmic trafficking inhibition. Virology 487:19-26
Ciomperlik, Jessica J; Basta, Holly A; Palmenberg, Ann C (2015) Three cardiovirus Leader proteins equivalently inhibit four different nucleocytoplasmic trafficking pathways. Virology 484:194-202
Bacot-Davis, Valjean R; Ciomperlik, Jessica J; Basta, Holly A et al. (2014) Solution structures of Mengovirus Leader protein, its phosphorylated derivatives, and in complex with nuclear transport regulatory protein, RanGTPase. Proc Natl Acad Sci U S A 111:15792-7
Basta, Holly A; Ashraf, Shamaila; Sgro, Jean-Yves et al. (2014) Modeling of the human rhinovirus C capsid suggests possible causes for antiviral drug resistance. Virology 448:82-90
Basta, Holly A; Palmenberg, Ann C (2014) AMP-activated protein kinase phosphorylates EMCV, TMEV and SafV leader proteins at different sites. Virology 462-463:236-40
Basta, Holly A; Sgro, Jean-Yves; Palmenberg, Ann C (2014) Modeling of the human rhinovirus C capsid suggests a novel topography with insights on receptor preference and immunogenicity. Virology 448:176-84
Petty, Ryan V; Basta, Holly A; Bacot-Davis, Valjean R et al. (2014) Binding interactions between the encephalomyocarditis virus leader and protein 2A. J Virol 88:13503-9
Basta, Holly A; Bacot-Davis, Valjean R; Ciomperlik, Jessica J et al. (2014) Encephalomyocarditis virus leader is phosphorylated by CK2 and syk as a requirement for subsequent phosphorylation of cellular nucleoporins. J Virol 88:2219-26
Bacot-Davis, Valjean R; Palmenberg, Ann C (2013) Encephalomyocarditis virus Leader protein hinge domain is responsible for interactions with Ran GTPase. Virology 443:177-85
Petty, Ryan V; Palmenberg, Ann C (2013) Guanine-nucleotide exchange factor RCC1 facilitates a tight binding between the encephalomyocarditis virus leader and cellular Ran GTPase. J Virol 87:6517-20

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