Herpesviruses have developed strategies to counteract host defenses so as to allow viruses to infect cells and result in a latent or persistent infection. The goal of this project is to identify and determine the function of herpesvirus proteins that interact with host cell proteins to influence the course of infection. These proteins may allow us to identify new molecules that are important in the human immune system. Programmed cell death (apoptosis) is an antiviral defense mechanism used by the host to eliminate virus-infected cells. Some viruses encode proteins that induce cell death that may allow them to exit from the cells that they infect. In collaboration with investigators in the LID, we have determined the mechanism for how a protein encoded by an RNA virus induces programmed cell death. This virus, Langat virus, causes encephalitis in mice and is a member of the flavivirus group which includes viruses such as the hepatitis C virus. We have found that a protein encoded by Langat virus, binds to a cellular protein (caspase-8) and induces cell death. Other viruses, which cause chronic infections, encode proteins that inhibit cell death which may allow the cells infected with the viruses to avoid destruction by the host's immune system. We have studied the mechanism by which a protein encoded by a human poxvirus, molluscum contagiosum, prevents cell death. Molluscum contagiosum is a frequent cause of skin lesions in children and can cause disfiguring lesions in immunosuppressed patients. We found that a protein encoded by this virus can inhibit cell death and determined which regions of the protein are important for this activity. We have also studied the cellular receptors that herpes simplex virus uses to enter cells. We found that there is a polymorphism (sequence difference) in one of the receptors for herpes simplex virus. We also found a polymorphism in a cellular protein that normally interacts with one of the herpes simplex virus receptors. These polymorphisms, however, did not correlate with the ability of a person to become infected by the virus or with the frequency of symptomatic or asymptomatic infection. Finally we have studied how a cellular protein, interleukin 17, modulates viral infection. We found that expression of interleukin 17 by the vaccinia virus enhanced the virulence of the virus and inhibited the ability of natural killer cells to control the virus infection.
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