EBV is a human gammaherpesvirus that is associated with both lymphoid and epithelial malignancies. The virus establishes persistent infections in almost all adults and the role that it plays in tumorigenesis is complex. Individuals who are immunosuppressed, particularly those infected with the human immunodeficiency virus (HIV), are at increased risk of developing EBV-associated malignancies. Part of this increased risk probably reflects a loss of control of replication of virus and an increase in virus load. The long term goal of this research is to understand how virus spreads and amplifies between and within hosts and to determine the roles that individual virus proteins play in the process. Five glycoproteins in the EBV envelope, gp350/220, gH, gL, gp42 and BMRF2, have been implicated as playing different roles in entry of B cells and epithelial cells. The immediate goals of this application are to evaluate the interactions of the glycoproteins with cell receptors and coreceptors and to determine their significance to virus infection.
Aim one will examine the role that two part gHgL complexes and three part gHgl_gp42 complexes play in cell tropism and trafficking of virus between B cells and epithelial cells. Mutational analysis will be made of gH sequences to discriminate regions that are important to infection of epithelial cells but not B cells from regions that are important for entry into both. The stoichiometry of the gH complexes will be used to identify the origin of virus shed in the oropharynx, the identity of the gHgL receptor on epithelial cells will be sought and its potential role in transfer of virus from B cells to epithelial cells in close contact will be evaluated.
Aim two will evaluate a role for the complement receptor type 2 (CR2) in post attachment events and in susceptibility of premalignant or malignant epithelial cells. Effects of deleting the cytoplasmic tail of CR2 on delivery of virus to the nucleus of the cell will be examined and the expression of CR2 on epithelial lesions ranging from mild dysplasia to invasive carcinoma will be determined.
Aim three will determine the role that the RGD motif of the BMRF2 protein plays in infection of polarized epithelial cells. Recombinant viruses that lack BMRF2 or expresses a BMRF2 protein in which RGD sequences have been mutated will be made in the context of an EBV Bac and their phenotypes will be examined. Understanding how EBV targets cells that become malignant is important for development of ways to prevent the process.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
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Special Emphasis Panel (ZDE1-PZ (08))
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Rodriguez-Chavez, Isaac R
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Louisiana State University Hsc Shreveport
Schools of Medicine
United States
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DiGiuseppe, Stephen; Bienkowska-Haba, Malgorzata; Guion, Lucile G et al. (2017) Cruising the cellular highways: How human papillomavirus travels from the surface to the nucleus. Virus Res 231:1-9
Chesnokova, Liudmila S; Valencia, Sarah M; Hutt-Fletcher, Lindsey M (2016) The BDLF3 gene product of Epstein-Barr virus, gp150, mediates non-productive binding to heparan sulfate on epithelial cells and only the binding domain of CD21 is required for infection. Virology 494:23-8
Hutt-Fletcher, Lindsey M (2015) EBV glycoproteins: where are we now? Future Virol 10:1155-1162
Nawandar, Dhananjay M; Wang, Anqi; Makielski, Kathleen et al. (2015) Differentiation-Dependent KLF4 Expression Promotes Lytic Epstein-Barr Virus Infection in Epithelial Cells. PLoS Pathog 11:e1005195
Jiang, Ru; Ekshyyan, Oleksandr; Moore-Medlin, Tara et al. (2015) Association between human papilloma virus/Epstein-Barr virus coinfection and oral carcinogenesis. J Oral Pathol Med 44:28-36
Wang, Hong-Bo; Zhang, Hua; Zhang, Jing-Ping et al. (2015) Neuropilin 1 is an entry factor that promotes EBV infection of nasopharyngeal epithelial cells. Nat Commun 6:6240
Chesnokova, Liudmila S; Ahuja, Munish K; Hutt-Fletcher, Lindsey M (2014) Epstein-Barr virus glycoprotein gB and gHgL can mediate fusion and entry in trans, and heat can act as a partial surrogate for gHgL and trigger a conformational change in gB. J Virol 88:12193-201
Chesnokova, Liudmila S; Hutt-Fletcher, Lindsey M (2014) Epstein-Barr virus infection mechanisms. Chin J Cancer 33:545-8
Birdwell, Christine E; Queen, Krista J; Kilgore, Phillip C S R et al. (2014) Genome-wide DNA methylation as an epigenetic consequence of Epstein-Barr virus infection of immortalized keratinocytes. J Virol 88:11442-58
Hutt-Fletcher, Lindsey M (2014) Epstein-Barr virus replicating in epithelial cells. Proc Natl Acad Sci U S A 111:16242-3

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