Cytomegalovirus is the leading infectious cause of birth defects 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 cancers including Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin lymphoma, and post-transplant lymphoproliferative disease. Human CMV and EBV naturally 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 for vaccines for their human counterparts. We are using various approaches including soluble recombinant proteins, virus-like particles, recombinant virus vectors expressing viral proteins, and replication defective viruses as vaccines. We have been using an animal model, rhesus monkey EBV in rhesus macaques, to compare various candidate EBV vaccines. Rhesus EBV causes a similar disease in monkeys as EBV does in humans and the viruses have the same number of virus genes that have virtually the same activities. We are currently comparing vaccines to different combinations of rhesus EBV glycoproteins. We have vaccinated the animals and recently challenged them to try to determine which glycoproteins are most important for protection from infection. We have also developed a candidate vaccine virus for rhesus CMV in which we deleted a protein from the virus that is essential for virus growth. The resulting replication-defective virus lacks one viral protein, glycoprotein L (gL), and replicates only in cells expressing rhesus CMV gL. In addition, noncomplementing cells infected with the replication-defective rhesus CMV produced glycoprotein B, the major target of neutralizing antibodies, at levels similar to those observed in cells infected with wild-type virus. We are testing this candidate vaccine in rhesus monkeys. The prototype strain of rhesus CMV is termed 68-1. This strain has been used in studies of pathogenesis and vaccine development. We determined the complete sequence of a region of rhesus CMV 68-1 which includes several proteins important for host cell tropism, directly from the origin urine from which the virus was isolated in 1968. We compared the sequence of the unpassaged rhesus CMV 68-1 virus with laboratory passaged virus currently in use in the United States. The sequence of laboratory passaged virus shows insertions, deletions, and stop codons in several genes compared with the unpassaged isolate. Virus genes important for cellular tropism and for immune evasion were the most common sites of mutations in laboratory isolates of the virus.

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9
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2014
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Cohen, Jeffrey I (2018) Vaccine Development for Epstein-Barr Virus. Adv Exp Med Biol 1045:477-493
Li, Qingxue; Bu, Wei; Gabriel, Erin et al. (2017) HLA-DQ?1 alleles associated with Epstein-Barr virus (EBV) infectivity and EBV gp42 binding to cells. JCI Insight 2:e85687
Burbelo, Peter D; Gunti, Sreenivasulu; Keller, Jason M et al. (2017) Ultrarapid Measurement of Diagnostic Antibodies by Magnetic Capture of Immune Complexes. Sci Rep 7:3818
Cohen, Jeffrey I (2017) GATA2 Deficiency and Epstein-Barr Virus Disease. Front Immunol 8:1869
Coghill, Anna E; Bu, Wei; Nguyen, Hanh et al. (2016) High Levels of Antibody that Neutralize B-cell Infection of Epstein-Barr Virus and that Bind EBV gp350 Are Associated with a Lower Risk of Nasopharyngeal Carcinoma. Clin Cancer Res 22:3451-7
Bu, Wei; Hayes, Gregory M; Liu, Hui et al. (2016) Kinetics of Epstein-Barr Virus (EBV) Neutralizing and Virus-Specific Antibodies after Primary Infection with EBV. Clin Vaccine Immunol 23:363-9
Li, Qingxue; Fischer, Elizabeth; Cohen, Jeffrey I (2016) Cell Surface THY-1 Contributes to Human Cytomegalovirus Entry via a Macropinocytosis-Like Process. J Virol 90:9766-9781
Li, Qingxue; Wilkie, Adrian R; Weller, Melodie et al. (2015) THY-1 Cell Surface Antigen (CD90) Has an Important Role in the Initial Stage of Human Cytomegalovirus Infection. PLoS Pathog 11:e1004999
Kanekiyo, Masaru; Bu, Wei; Joyce, M Gordon et al. (2015) Rational Design of an Epstein-Barr Virus Vaccine Targeting the Receptor-Binding Site. Cell 162:1090-100
Cohen, Jeffrey I (2015) Epstein-barr virus vaccines. Clin Transl Immunology 4:e32

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