TNF-alpha After Anterior Chamber Inoculation of HSV-1

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DESCRIPTION (provided by applicant): Anterior chamber (AC) inoculation of euthymic BALB/c mice with the KOS strain of HSV-1 results in retinitis of the uninjected eye only. Timing of virus entry into the suprachiasmatic nucleus (SCN) of the hypothalamus appears to be crucial in determining whether mice develop bilateral retinitis. After AC inoculation of HSV-1 into one eye, virus enters the optic nerve and retina of the contralateral eye by spreading from the ipsilateral SCN. Although virus infects the contralateral SCN, it does not spread from there to the optic nerve and retina of the injected eye. If virus can be contained in the SCN, such containment would likely prevent virus infection of the retina of the uninjected eye. My preliminary studies suggest that production of tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, in the SCN is important for limitation of virus spread and possibly for sparing of the retina of the injected eye. Using immunohistochemistry, immunofluorescence, plaque assays, and molecular cloning methods, I plan to: (1) determine the role of TNF-alpha in the eyes and brain of HSV-1 infected BALB/c mice by blocking TNF-a, (2) identify the cells in the SCN and in the injected eye that produce TNF-alpha, and (3) construct a non-defective recombinant of HSV-1 that can be induced to express TNF-alpha. The results of these studies will provide a further understanding of the role of TNF-alpha in the central nervous system during viral infection, and perhaps open the door for the development of a cytokine-based anti-viral therapy to assist the immune system in early clearance of virus.