Understanding the mechanisms of axonal transport of neurotropic viruses is the key to understanding and controlling their spread in the nervous system. To multiply and spread, to move initially from the site of entry and later to the site of release, Herpes simplex virus (HSV) must use neuronal host cell proteins and mechanisms. Our understanding of the interplay of specific viral proteins that piggyback on the mechanisms and of the neuronal proteins that are exploited, is critical but almost nonexistent. In this application we continue to focus on the anterograde transport of HSV. Based on our previous results, our hypothesis is that the nucleocapsid and envelope components of HSV are independently transported in the axon and that the components require specific kinesin related proteins. 1) We have begun to examine the transport of the nucleocapsid and envelope components. To do this we have developed two viral mutant strains and revertants that will facilitate our research into these transport mechanisms. 2) In this proposal we shall continue these studies and carry out co-immunoprecipitation assays to identify the motor proteins associated with the nucleocapsid component. 3) We shall also determine whether or not the virus egresses from the cell by budding, after the envelope proteins are delivered to the axon membrane and the nucleocapsids cluster near that region of membrane. These results will provide important new cell biological information about the recognition signals of particular organelles. They will also have significant clinical benefits. The anterograde transport of HSV to the cornea in human herpetic keratitis results in severe consequences, including corneal scars, glaucoma and possibly encephalitis. Our results will provide new insight into the identification of viral and host proteins necessary for viral envelope and nucleocapsid transport and a rational basis for the design of innovative antiviral drugs for prevention and intervention. Furthermore, the genome of HSV can be altered to serve as a vector for introduction of novel genes into the nervous system. Our results will elucidate the mechanisms that target the vector to particular neuron types and to particular regions of infected neurons.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY008773-26
Application #
6875559
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Shen, Grace L
Project Start
1978-07-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
26
Fiscal Year
2005
Total Cost
$303,000
Indirect Cost
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Draper, Jolene M; Stephenson, Graham S; LaVail, Jennifer H (2014) In vivo HSV-1 DNA transport studies using murine retinal ganglion cells. Methods Mol Biol 1144:283-92
LaVail, J H; Tauscher, A N; Sucher, A et al. (2007) Viral regulation of the long distance axonal transport of herpes simplex virus nucleocapsid. Neuroscience 146:974-85
LaVail, Jennifer H; Tauscher, Andrew N; Hicks, James W et al. (2005) Genetic and molecular in vivo analysis of herpes simplex virus assembly in murine visual system neurons. J Virol 79:11142-50
Harrabi, Ons; Tauscher, Andrew N; LaVail, Jennifer H (2004) Temporal expression of herpes simplex virus type 1 mRNA in murine retina. Curr Eye Res 29:191-4
Whitehead, John L; Ohara, Peter T; Tauscher, Andrew N et al. (2003) A procedure to deliver herpes simplex virus to the murine trigeminal ganglion. Brain Res Brain Res Protoc 12:60-6
LaVail, Jennifer H; Tauscher, Andrew N; Aghaian, Elda et al. (2003) Axonal transport and sorting of herpes simplex virus components in a mature mouse visual system. J Virol 77:6117-26
Ohara, P T; Tauscher, A N; LaVail, J H (2001) Two paths for dissemination of Herpes simplex virus from infected trigeminal ganglion to the murine cornea. Brain Res 899:260-3
Ohara, P T; Chin, M S; LaVail, J H (2000) The spread of herpes simplex virus type 1 from trigeminal neurons to the murine cornea: an immunoelectron microscopy study. J Virol 74:4776-86
Bearer, E L; Breakefield, X O; Schuback, D et al. (2000) Retrograde axonal transport of herpes simplex virus: evidence for a single mechanism and a role for tegument. Proc Natl Acad Sci U S A 97:8146-50
Bearer, E L; Schlief, M L; Breakefield, X O et al. (1999) Squid axoplasm supports the retrograde axonal transport of herpes simplex virus. Biol Bull 197:257-8

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