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Neuroscience Graduate Program at UCSF
Mutant Strains of Herpes Simplex Virus Used as Probes for Studying Axonal Transport
Our laboratory is interested in the intracellular transport of organelles, for example, retrograde moving endosomes with trophic signaling molecules or anterograde moving vesicles containing enzymes for synaptic function. We have adopted the strategy of investigating the intracellular transport of Herpes simplex virus type 1 (HSV) as a model for the transport of endogenous organelles. Not only do various mutants allow us to compare the components of the virus that are essential for transport, but they also permit genetic analysis of the molecular basis for the transport ability.
HSV-1 is the most common cause of infectious blindness in the U.S. Approximately 500,000 cases of ocular herpetic keratitis, as well as 40,000 cases of sensory hearing loss due to cytomegalovirus, are reported annually in the U.S. The clinical significance of HSV ocular infections in particular, involving CMV and HSV retinopathy in immunocompromised patients, motivates us to focus on understanding the host neuronal response to herpesvirus infections, and in particular the targeted axonal transport of HSV. Human ocular HSV infection results from the spread of virus from sensory nerve endings to the trigeminal ganglion and CNS or from retinal vascular transfer and infection of the retina. HSV gains access to neuronal cytoplasm and pirates host cell machinery, cytoplasmic motors and cytoskeletal elements for retrograde transport to the nucleus. In the nucleus, the virus either replicates or assumes a latent state from which it may reactivate later in response to peripheral stimuli. The anterograde transport of newly-synthesized HSV is essential for transmission of virus through the nervous system. However, molecular and cell biological features of anterograde transport of the virus have yet to be well-defined. The goal of our research is to provide 1) detailed basic cell biology and molecular information about the viral particle that is anterogradely transported; 2) the mechanisms by which HSV is anterograde axonally transported; and 3) the viral gene(s) that are required for anterograde transport. Retinal ganglion cells are used as the model, because virus moving in the anterograde direction can be distinguished from that moving in the retrograde direction. We hypothesize that HSV uses normal intracellular targeting mechanisms to accomplish its transport and targeting. We have begun to unravel the molecular signals involved in the infection and transport of the herpes virus, as well as the mechanisms of infection of other clinically significant neurotropic viruses, such as cytomegalovirus, varicella-zoster virus.
Ohara, P.T., Chin, M. S. and J.H. LaVail. The spread of Herpes Simplex Virus type 1 from trigeminal neurons to cornea: an immunoelectron microscopy study. J. Virol. 74 (10): 4776-4786, 2000.
Bearer, E.L., Breakefield, X.O., Schuback, D., Reese, T.S. and J.H. LaVail. Retrograde axonal transport of herpes simplex virus: evidence for a single mechanism and a role for tegument.. P.N.A.S. USA, 97 (14): 8146-815, 2000.
LaVail, J.H., Tauscher, A.N., Aghaian, E., Harrabi, Ons, Sidhu, S.S. Axonal transport and sorting of herpes simplex virus components in mature mouse visual system. J. Virol. 77 (11), 6117-6126, 2003.
Harrabi, O., Tauscher, A.N. and LaVail, J.H. Temporal expression of herpes simplex virus type 1 mRNA in murine retina. Curr. Eye Res. 29 (2-3): 191-194, 2004.
LaVail, J.H., Tauscher, A.N., Hicks, J.W., Harrabi, O., Melroe, G.T. and D.M. Knipe. Genetic and molecular in vivo analysis of herpes simplex virus assembly in murine visual system neurons. J. Virol. 79 (17): 11142-11150, 2005.
Duffy C, LaVail JH, Tauscher AN, Wills EG, Blaho JA, Baines JD. Characterization of a UL49-null mutant: VP22 of herpes simplex virus type 1 facilitates viral spread in cultured cells and the mouse cornea. J. Virol. 80(17):8664-75, 2006.
LaVail, J.H., Tauscher, A.N., Sucher, A, Harrabi, O. and R. Brandimarti. The Us9 tegument protein of Herpes simplex virus is necessary for encephalitic spread. Neuroscience. 146: 974-985, 2007.
Jennifer LaVail, Ph.D.
Phone
415-476-1694
Physical Address
513 Parnassus
1325-HSW
Mailing Address
UCSF, 513 Parnassus
Box 0452
San Francisco, CA 94143-0452
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Box 0452
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