Foamy viruses comprise a subfamily of retroviruses with many unique features. They are the most ancient vertebrate RNA viruses and are ubiquitous in non-human primates. They are also known to infect small numbers of humans. Aspects of their replication pathway are quite similar to that of the hepadnaviruses, for example, conversion of RNA to a DNA genome during assembly and requirement for only a single capsid protein. However, unlike members of both groups which can cause cancers and immunodeficiencies, foamy viruses are non-pathogenic. This feature makes them attractive candidates for gene therapy vectors, and development of foamy viral vectors is underway. Such foamy virus vectors show promise for cancer, infectious diseases and genetic disorders because of their broad host range and ability to infect early stem cells. However, there are many gaps in our knowledge of how these viruses replicate. The goal of this work is to increase understanding of foamy virus assembly and gene regulation. We will focus on 3 aspects;viral capsid assembly and association with viral glycoproteins, packaging of the viral genome and enzymes, and regulation of splicing of the viral Pol mRNA. At each of these replication steps, foamy viruses are different from both orthoretroviruses and hepadnaviruses. We will take both molecular genetic and cell biology approaches to study viral replication, including analysis of viral mutants, yeast 2-hybrid assays, immunofluorescence and immunoelectron microscopy.
In Aim 1, we will analyze the cellular sites for viral assembly, the host and viral protein interactions that are required, and the regions of the structural protein (Gag) that interact with the viral glycoproteins to allow viral budding.
In Aim 2, we will determine the regions of Gag that are important for encapsidation of the viral genome and the viral Pol protein (that encodes all of the viral enzymes).
In Aim 3, we will examine how splicing of the unique mRNA encoding Pol is regulated. Completion of these Aims will help in the design of foamy virus vectors and increase our knowledge about the diverse pathways possible for retroviral replication.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA018282-35
Application #
7997232
Study Section
Virology - B Study Section (VIRB)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1978-12-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2013-01-31
Support Year
35
Fiscal Year
2011
Total Cost
$471,252
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Matsen 4th, Frederick A; Small, Christopher T; Soliven, Khanh et al. (2014) A novel Bayesian method for detection of APOBEC3-mediated hypermutation and its application to zoonotic transmission of simian foamy viruses. PLoS Comput Biol 10:e1003493
Stenbak, Carolyn R; Craig, Karen L; Ivanov, Sergei B et al. (2014) New World simian foamy virus infections in vivo and in vitro. J Virol 88:982-91
Feeroz, Mostafa M; Soliven, Khanh; Small, Christopher T et al. (2013) Population dynamics of rhesus macaques and associated foamy virus in Bangladesh. Emerg Microbes Infect 2:e29
Jackson, Dana L; Lee, Eun-Gyung; Linial, Maxine L (2013) Expression of prototype foamy virus pol as a Gag-Pol fusion protein does not change the timing of reverse transcription. J Virol 87:1252-4
Lee, Eun-Gyung; Stenbak, Carolyn R; Linial, Maxine L (2013) Foamy virus assembly with emphasis on pol encapsidation. Viruses 5:886-900
Soliven, Khanh; Wang, Xiaoxing; Small, Christopher T et al. (2013) Simian foamy virus infection of rhesus macaques in Bangladesh: relationship of latent proviruses and transcriptionally active viruses. J Virol 87:13628-39
Lee, Eun-Gyung; Sinicrope, Amber; Jackson, Dana L et al. (2012) Foamy virus Pol protein expressed as a Gag-Pol fusion retains enzymatic activities, allowing for infectious virus production. J Virol 86:5992-6001
Yu, Shuyuarn F; Lujan, Phillip; Jackson, Dana L et al. (2011) The DEAD-box RNA helicase DDX6 is required for efficient encapsidation of a retroviral genome. PLoS Pathog 7:e1002303
Lee, Eun-Gyung; Roy, Jacqueline; Jackson, Dana et al. (2011) Foamy retrovirus integrase contains a Pol dimerization domain required for protease activation. J Virol 85:1655-61
Lee, Eun-Gyung; Kuppers, Daniel; Horn, Megan et al. (2008) A premature termination codon mutation at the C terminus of foamy virus Gag downregulates the levels of spliced pol mRNA. J Virol 82:1656-64

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