Primary infection with varicella-zoster virus (VZV) causes chickenpox, and reactivation of the virus from latency results in zoster. The purpose of this project is to study the molecular pathogenesis and latency of VZV and to identify targets for novel therapies. We have constructed a VZV that expresses the herpes simplex virus type 2 (HSV-2) glycoproteins B and D. In collaboration with investigators at St. Louis University we have shown that animals vaccinated with VZV that expresses the HSV-2 glycoproteins produce antibody that can neutralize infection with HSV-2. When these animals were challenged with wild-type HSV-2 they had reduced herpes lesions, reduced shedding of HSV-2, and reduced mortality compared with control animals that had not been vaccinated, or were vaccinated with VZV not expressing the HSV-2 glycoproteins. We also constructed a VZV that expresses the simian immunodeficiency virus (SIV) envelope protein (glycoprotein 160). In collaboration with investigators at the Emory Vaccine Center we showed that rhesus macaques vaccinated with this virus produce nonneutralizing antibodies to SIV and develop little or no cytotoxic T cell responses to SIV. When these animals were challenged with SIV, the vaccinated animals had increased levels of SIV replication, more rapid loss of CD4 cells, and increased progression to AIDS compared with control animals that had not been vaccinated, or were vaccinated with VZV not expressing the SIV envelope protein. These experiments suggest that some candidate AIDS vaccines may actually be detrimental compared to control vaccines. In collaboration with investigators at Hospital Necker in Paris we showed that a child who had received gene therapy for severe combined immunodeficiency disease had varicella-zoster virus in a T lymphocyte cell clone that had been isolated from the blood. This suggests that the varicella-zoster virus may have induced a transient immunodeficiency state that helped to allow an abnormal clone of T lymphocytes to proliferate in the blood.
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