Herpesvirus Pathogenesis and Vaccine Development

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Abstract

While some individuals who become infected with herpesviruses are asymptomatic, others have moderate or severe symptoms. One factor that might explain differences in symptoms could be sequence differences (polymorphisms) in cellular proteins. We are determining if polymorphisms in cellular proteins correlate with infectivity of herpesviruses or severity of herpesvirus disease. Previously, we identified new polymorphisms in one of the three herpes simplex virus receptors in humans, and in a protein that binds to another of these receptors. Analysis of our patient population did not show a correlation with these polymorphisms and HSV infection or degree of symptoms.[unreadable] [unreadable] We are trying to identify novel or known viruses as causes of diseases of uncertain etiology. Blood and tissues from patients are being examined by sensitive PCR tests in an attempt to find new or known viruses that are responsible for the diseases. Previously, we evaluated biopsies from three patients who presented with fever and enlarged lymph nodes; some of these persons had fatigue and elevated levels of liver enzymes. Serologic tests for a variety of viruses were negative. Using or PCR tests we amplified DNA from the lymph nodes and sequencing showed that the patients were infected with human herpesvirus 6. Subsequently, immunohistochemistry using antibody to human herpesvirus 6 identified the virus envelope glycoprotein in virus inclusion bodies in the lymph nodes. [unreadable] [unreadable] Cytomegalovirus causes congenital disease which can result in deafness and mental retardation in neonates, and can cause severe viral pneumonia and colitis in transplant recipients and sight-threatening retinitis in patients with AIDS. Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with a number of malignancies including Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin?s disease, and post-transplant lymphoproliferative disease. Human CMV and EBV infect humans, but not small animals or nonhuman primates. The best models currently available for CMV and EBV are rhesus monkey CMV and EBV. The goal of this study is to develop an effective vaccine for these rhesus viruses and to use these as a model vaccines for their human counterparts. We are using various approaches including soluble recombinant proteins, recombinant virus vectors expressing viral proteins, and replication defective viruses as vaccines.