Jennifer LaVail, PhD

Professor, Anatomy/Opthalmology

Research Summary:

Axonal Transport Mechanisms of Herpes Simplex Virus in CNS Neurons

(415) 476-1694

lavailj@vision.ucsf.edu

Additional Websites:Laboratory Website Neuroscience Graduate Program Biomedical Sciences Graduate Program

View Selected Publications

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Textbooks descriptions of the maturation of infectious Herpes simplex virus (HSV) have depended almost entirely on results obtained in infected, non-polarized cells in vitro . We have begun to examine viral maturation in neurons in vivo - clinically a more relevant cell type - and have found that the process is significantly more complex. To enter into neurons and the CNS, HSV must enter the dendritic process of a neuron host cell and transport the viral DNA into the nucleus where it starts new replication. The subsequent transport of virion subassemblies of envelope and capsid to central axon terminals and their assembly and release from the host cell to infect other neurons are currently critical questions for neurovirologists.

One goal is to identify viral and host cell signaling molecules for directed transport. To carry out these experiments, we have developed a novel in vivo assay to study the anterograde axonal transport of assembly and release of HSV from intact mature neurons. Our findings thus far support the subassembly model of viral transport in mature neurons. The kinetics of delivery and transport of the viral DNA are the current focus of our lab.

Another target of our research is to define the viral proteins involved in spread of HSV from infected trigeminal axons that terminate in the cornea. We developed a second murine model to study this neuron-to-epithelial spread of virus as a way of understanding the cascade of steps in recurrent herpetic keratitis. This procedure involved injection of HSV into the trigeminal ganglion and spread of virus from sensory neurons to the cornea and within the cornea (Ohara et al. 2000). We can now study HSV movement from infected neurons into epithelial tissues reproduces at least some of the steps that occur during recurrent HSV infection in the human eye. We have made some striking observations: HSV moves in a directed fashion from axon terminals into basal corneal cells. After replication, new virus is sorted to the apical surfaces of the basal cells. It then spreads laterally to the wing and squamous cells. This system allows us to study the sorting in vivo for the first time. Using a panel of HSV glycoprotein (viral envelope proteins) mutants of HSV we can begin to unravel the molecular requirements of receptors and ligands.

Selected Publications

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., Schlief, M.L., Breakefield, X.O., Schuback, D.E., Reese, T.S. and J.H. LaVail Squid axoplasm supports the retrograde axonal transport of Herpes simplex virus. Biol. Bull. 197: 257-258, 1999.

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.

Ohara, P.T., Tauscher, A.N. and J.H. LaVail. Two paths for dissemination of herpes simplex virus from infected trigeminal ganglion to the murine cornea. Brain Res. 899 (1/2): 260-263, 2001.

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.

Whitehead, J.L., Ohara, P.T., Tauscher, A.N., J. H. LaVail. A procedure to estimate the spread of herpes simplex virus after delivery to the murine trigeminal ganglion. Brain Res. Protocols, 12/1, 60-66, 2003.

Sidhu, S.S., Mengistab, A.T., Tauscher, A.N., LaVail, J. and C. Basbaum. The microvesicle as a vehicle for EMMRPRIN in tumor-stromal interactions. Oncogene 23: 956-963, 2004.

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), 191-193, 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).