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Abstract

Grant Number:	1R03NS050788-01
Project Title:	Screening of Epstein Barr Virus Replication (RMI)

PI Information:	Name	Email	Title
	KIEFF, ELLIOTT D.	ekieff@rics.bwh.harvard.edu	PROFESSOR

Abstract: DESCRIPTION (provided by applicant): Long term objective is to identify small molecules which can eradicate latent EBV genomes and latently infected cells. The specific objective is to identify chemical candidates that functionally inhibit EBNA1 in cells and in vitro. These molecules could be used to validate the importance of targeting EBNA1 for the elimination of EBV episomes and for halting the growth of latency III infected lymphocytes, in culture or in experimental models. This would provide a compelling model and perhaps a lead compound for approaches to the therapy or prevention of EBV associated PTLD, AIDS associated lymphoma. Although prevalent in all human populations, EBV is an important cause of lymphoma and in immune compromised people Disease (PTLD), various B and T cell Lymphoma (L) and Hodgkin's Lymphoma (HL). EBV replicates in oropharyngeal epithelial cells and establish latency in B lymphocytes. In B cells EBV can establish 3 types of latency. Latency Ill, EBV expresses 6 EB Nuclear antigens (EBNAs) and two integral membrane proteins (LMP1 and 2) and causes lymphocyte proliferation, which is indistinguishable from PTLD. Normally, latency type lll cells are recognized by T lymphocytes and are readily eliminated as immune response develop. Some infected B cells persist in latency type II, wherein only EBNA1, LMP1 and LMP2 are expressed or, in latency type I, wherein only EBAN1 is expressed. EBNA1 is not processed by proteasome pathways and thereby escapes recognition by CD8 cytotoxic T cells. EBNA1 is the only protein required for EBV DNA persistence as extrachromosomal episomes. EBNA1 binds to cognate sequences in oriP and to chromosomes, enabling EBV DNA to be replicated, maintained, transcribed. Therefore, inhibition of EBNA1 function is likely to be efficient way to eradicate EBV infected cells from body.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
Epstein Barr virus, drug discovery /isolation, drug screening /evaluation, latent virus infection, small molecule, virus replication
B lymphocyte, gene expression, host organism interaction, immunopharmacology, plasmid, virus antigen, virus genetics, virus infection mechanism
high throughput technology

Institution:	BRIGHAM AND WOMEN'S HOSPITAL
	RESEARCH ADMINISTRATION
	BOSTON, MA 02115
Fiscal Year:	2004
Department:
Project Start:	30-SEP-2004
Project End:	29-SEP-2005
ICD:	NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG:	ZNS1

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