The Alphavirus genus in the Togaviridae family contains a variety of widely distributed important human and animal pathogens. Venezuelan (VEEV), eastern (EEEV) and western (WEEV) equine encephalitis viruses represent a serious public health threat in the US and can be applied by bioterrorists. However, to date, neither effective antiviral nor safe and efficient vaccines have been developed for preventing any of these infections. The existing experimental vaccines are either of poor efficacies or demonstrate very strong adverse reactions in humans. Our recent studies of the molecular mechanism of alphavirus RNA packaging led to understanding of structure and function of the alphavirus RNA-specific packaging signal, which is present in the genomes of other encephalitogenic alphaviruses and recognized by both homologous and capsid proteins. These data will be applied in the proposed research to develop fundamentally new strategies of designing live alphavirus variants possessing irreversible, highly attenuated phenotypes, but producing virus-specific antigens, required for induction of sterilizing immunity as efficiently as a wt virus. By introducing multiple, rationally designed mutations into capsid protein or newly identified universal RNA packaging signal, we will develop alphaviruses that retain high levels of RNA replication, and production of structural proteins which are released either mostly (strategy 1) or exclusively (strategy 2) in the form of non-infectious, genome-free virus-like particles and, thus, develop no viremia in vivo. These viruses will be capable of inducing a balanced combination of cellular immune response and high levels of neutralizing antibodies.

Public Health Relevance

The research proposal is aimed to develop fundamentally new strategies of designing live alphavirus vaccines demonstrating irreversible, highly attenuated phenotype, but producing virus-specific antigens, required for induction of sterilizing immunity as efficiently as wt viruses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI095449-03
Application #
8602826
Study Section
Special Emphasis Panel (ZRG1-IDM-B (02))
Program Officer
Repik, Patricia M
Project Start
2012-02-01
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
3
Fiscal Year
2014
Total Cost
$329,625
Indirect Cost
$104,625
Name
University of Alabama Birmingham
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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
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
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