HSV and Host Cell Contributions to Corneal Infection

University Of California San Francisco, San Francisco CA

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Abstract

The ability of a virus to usurp the normal cell biology of a host cell for viral replication and spread depends on both viral gene expression and host cell responses. The key to controlling viral invasion of an epithelium lies in understanding the mechanisms by which virus spreads within and between host cells. We shall focus on mechanisms by which Herpes simplex virus type 1 (HSV) invades and usurps the machinery of corneal epithelial cells. The available information about the regulation of HSV infection and spread in the cornea is limited. However, it is clear that at least three mechanisms are involved. 1) Free virus can enter the cornea from a distance, attach and fuse with a host cell plasma membrane and enter the cell (viral fusion mechanism). 2) A different mechanism is used for transfer of virions from an infected cell to coupled adjacent cells (cell-to-cell spread mechanism). 3) Finally, a less widely recognized mechanism involves the movement of virus in an infected cell as the cell moves from one location to another (translational mechanism). We hypothesize that viral envelope glycoproteins and host cell surface receptors play key roles in the spread of HSV in cornea in the first and second mechanisms, but not in the translational mechanism. We will use two mouse model systems: first, primary infection with virus delivered to the corneal surface injury; and second, a model of recurrent herpetic infection by viral delivery to the basal surface of the intact cornea via infected trigeminal ganglion cell axons. Using genetic, pharmacological and immunocytochemical tools, we shall define the contributions of viral fusion and cell-to-cell spread by their different sensitivity to mutations in the HSV envelope glycoproteins. The role of translocation of virally infected cells will be determined by delivering HSV as a pulse, using Valacyclovir to eliminate secondary cell infection. These in vivo experiments will provide fundamental, cell biological information about the transfer of HSV between squamous epithelial cells in vivo and the response of host cell junctions to injury. In addition, the results will also have significant clinical benefits. A better understanding of the differences between spread of virus after corneal injury and of the spread that results from reactivated HSV delivered to the cornea in human herpetic keratitis will focus attention on whether different strategies are required for treatment of initial as opposed to recurrent infections. Moreover, our results will lead to identification of viral and host proteins that are necessary for viral spread and a rational basis for the design of innovative antiviral drugs.