Persistent but benign infection with cytomegalovirus (CMV) is a nearly ubiquitous occurrence in most human populations. However, primary infection during pregnancy can lead to serious CNS disease in the developing fetus or newborn infant and reactivated disseminated infection causes retinitis in AIDS patients and life-threatening pneumonitis, or hepatitis and allograft rejection in immunosuppressed bone marrow and heart, lung, kidney, liver and pancreas transplant patients. CMV is also suspected of contributing to chronic vascular disease and obliterative bronchiolitis in transplant patients and possibly also to restenosis and atherosclerosis. Acute disseminated infection can be reduced but not eliminated by Ganciclovir treatment and resistant strains develop. HCMV is one of the largest and most complex of mammalian viruses and despite much progress in the molecular biology and identifying important genes of the virus in recent years, a great deal more basic research is needed to understand its cell biology and pathogenesis. In this project, we have undertaken a detailed analysis of the major immediate-early (MIE) genes of HCMV whose two principal gene products IE1 (IE72, UL123) and IE2(IE86, UL122) function to switch the cell into and out of latency and to prepare the cell for efficient productive lytic cycle infection. The focus of these studies encompasses control of MIE gene expression via the MIE enhancer domain, the role of IE1 in dispersing PML from its associated intra-nuclear bodies, called PML-oncogenic domains (PODs or ND10) and the pleotrophic roles of IE2 in positive and negative transcriptional control, post-translation regulation of cell cycle events and the switch from cellular to viral DNA replication. Specific projects in the present 5-year proposal include: (I) Analysis of the functional consequences of post-transcriptional interactions of IE2 with four potential cell cycle regulatory proteins p21, JAB1, APC2 and MAD2; (II) continued exploration of the role of PML, DAXX, SUMO and the PODs at very early times in the nucleus, including how IE1 and IE2 target to the PODS and the role of IE1 in removing SUMO from PML, in PML and SP100 repression, and in facilitating proper IE2 intranuclear localization; and (III) Evaluation of the viral and cellular protein components, functions and temporal interrelationships between four distinct subnuclear domains containing the IE2 protein, including three that are presumed to be MIE enhancer or Ori-Lyt associated forming """"""""IE transcription sites"""""""", pre-replication foci"""""""" (pre-RF) and mature viral DNA replication compartments (RC).

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology Study Section (VR)
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Beisel, Christopher E
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Johns Hopkins University
Schools of Medicine
United States
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Long, Simon Y; Latimer, Erin M; Hayward, Gary S (2016) Review of Elephant Endotheliotropic Herpesviruses and Acute Hemorrhagic Disease. ILAR J 56:283-96
Zong, Jian-Chao; Heaggans, Sarah Y; Long, Simon Y et al. (2015) Detection of Quiescent Infections with Multiple Elephant Endotheliotropic Herpesviruses (EEHVs), Including EEHV2, EEHV3, EEHV6, and EEHV7, within Lymphoid Lung Nodules or Lung and Spleen Tissue Samples from Five Asymptomatic Adult African Elephants. J Virol 90:3028-43
Zong, Jian-Chao; Latimer, Erin M; Long, Simon Y et al. (2014) Comparative genome analysis of four elephant endotheliotropic herpesviruses, EEHV3, EEHV4, EEHV5, and EEHV6, from cases of hemorrhagic disease or viremia. J Virol 88:13547-69
Richman, Laura K; Zong, Jian-Chao; Latimer, Erin M et al. (2014) Elephant endotheliotropic herpesviruses EEHV1A, EEHV1B, and EEHV2 from cases of hemorrhagic disease are highly diverged from other mammalian herpesviruses and may form a new subfamily. J Virol 88:13523-46
Ling, Paul D; Reid, Jeffrey G; Qin, Xiang et al. (2013) Complete Genome Sequence of Elephant Endotheliotropic Herpesvirus 1A. Genome Announc 1:e0010613
Atkins, Lisa; Zong, Jian-Chao; Tan, Jie et al. (2013) Elephant endotheliotropic herpesvirus 5, a newly recognized elephant herpesvirus associated with clinical and subclinical infections in captive Asian elephants (Elephas maximus). J Zoo Wildl Med 44:136-43
Stanton, Jeffrey J; Zong, Jian-Chao; Eng, Crystal et al. (2013) Kinetics of viral loads and genotypic analysis of elephant endotheliotropic herpesvirus-1 infection in captive Asian elephants (Elephas maximus). J Zoo Wildl Med 44:42-54
Zachariah, Arun; Zong, Jian-Chao; Long, Simon Y et al. (2013) Fatal herpesvirus hemorrhagic disease in wild and orphan asian elephants in southern India. J Wildl Dis 49:381-93
Stanton, Jeffrey J; Nofs, Sally A; Peng, Rongsheng et al. (2012) Development and validation of quantitative real-time polymerase chain reaction assays to detect elephant endotheliotropic herpesviruses-2, 3, 4, 5, and 6. J Virol Methods 186:73-7
Latimer, Erin; Zong, Jian-Chao; Heaggans, Sarah Y et al. (2011) Detection and evaluation of novel herpesviruses in routine and pathological samples from Asian and African elephants: identification of two new probosciviruses (EEHV5 and EEHV6) and two new gammaherpesviruses (EGHV3B and EGHV5). Vet Microbiol 147:28-41

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