Epstein-Barr virus (EBV) is a human herpesvirus that infects both B lymphocytes and epithelial cells. Depending upon cell type and differentiation state, infection leads to lytic replication with cell death or latent infection. Latent infections are associated with several epithelial- and B-cell malignancies. By identifying key cellular factors and pathways regulating EBV latency and lytic replication and drugs that affect their activities, we hope to develop "lytic induction" therapies for treating patients with EBV-associated cancers. The immediate- early BZLF1 and BRLF1 genes of EBV encode multifunctional proteins essential for lytic replication. While transcription from their promoters, Zp and Rp, respectively, is strongly silenced in latently infected cells, cell differentiation and factors activated by signaling pathways can induce their expression, leading to reactivation into lytic replication. We have identifled several physiologically relevant factors that play key roles in regulating this switch: ZEB1, ZEB2, p53, Oct-1, Oct-2, Smads via TGF-p signaling, and the Zp ZIIR element. We have preliminary data indicating important roles as well for HIF-1 a, Pax5, and Blimp-la and have identified 2 drugs, nufiin-3 and L-mimosine, that induce EBV reactivation via effects on some of these factors. We have developed a mouse model with a humanized immune system that can be use to examine factors affecting EBV-induced tumorigenesis and effects of drugs on growth and killing of EBV+ lymphomas. We have also identified a non-tumorigenic epithelial cell line, NOKs, in which we can study effects of differentiation state on EBV's life cycle. Here, we propose to determine: (i) how HIF-1 a, the ZEBs, PAX5, and Blimp-la play key roles in controlling EBV's latent-lytic balance in cells in culture, during differentiation of EBV+ NOKs and B cells, and in humanized mice;and (ii) whether nufiin-3 or L-mimosine together with HDAC inhibitors can efficiently reactivate EBV, leading to highly selective killing of some types of EBV+ cells lines in culture and tumors in humanized mice, especially when used in combination with ganciclovir, a nucleoside analog prodrug activated by a virus-encoded kinase. The findings obtained from these experiments will identify key cellular factors and pathways that regulate the balance between latency and lytic replication of EBV in epithelial and B cells, may identify effective lytic-inducing drugs for treating EBV-associated cancers, and may lead to a candidate vaccine for immunization against EBV by identifying an EBV mutant unable to establish viral latency. Drs. Kenney and Mertz collaborate extensively, including holding bimonthly joint research group meetings and co-authoring publications in which both labs made key contributions.
Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus associated with several types of cancers. This project is designed to identify drugs that effectively reactivate this virus out of latency into lytic replication to use for treating patients with EBV-associated cancers. This work may lead to a candidate vaccine for immunization against EBV.
|Park, Jung Wook; Nickel, Kwangok P; Torres, Alexandra D et al. (2014) Human papillomavirus type 16 E7 oncoprotein causes a delay in repair of DNA damage. Radiother Oncol 113:337-44|
|Wang, Lu; Zhao, Zibo; Meyer, Mark B et al. (2014) CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis. Cancer Cell 25:21-36|
|Kuzembayeva, Malika; Hayes, Mitchell; Sugden, Bill (2014) Multiple functions are mediated by the miRNAs of Epstein-Barr virus. Curr Opin Virol 7:61-5|
|Wang, Joseph Che-Yen; Nickens, David G; Lentz, Thomas B et al. (2014) Encapsidated hepatitis B virus reverse transcriptase is poised on an ordered RNA lattice. Proc Natl Acad Sci U S A 111:11329-34|
|Stein, Andrew P; Saha, Sandeep; Yu, Menggang et al. (2014) Prevalence of human papillomavirus in oropharyngeal squamous cell carcinoma in the United States across time. Chem Res Toxicol 27:462-9|
|Iempridee, Tawin; Reusch, Jessica A; Riching, Andrew et al. (2014) Epstein-Barr virus utilizes Ikaros in regulating its latent-lytic switch in B cells. J Virol 88:4811-27|
|Park, J W; Shin, M-K; Lambert, P F (2014) High incidence of female reproductive tract cancers in FA-deficient HPV16-transgenic mice correlates with E7's induction of DNA damage response, an activity mediated by E7's inactivation of pocket proteins. Oncogene 33:3383-91|
|Shrestha, Prabha; Sugden, Bill (2014) Identification of properties of the Kaposi's sarcoma-associated herpesvirus latent origin of replication that are essential for the efficient establishment and maintenance of intact plasmids. J Virol 88:8490-503|
|Vereide, D T; Seto, E; Chiu, Y-F et al. (2014) Epstein-Barr virus maintains lymphomas via its miRNAs. Oncogene 33:1258-64|
|Son, Jieun; Park, Jung Wook; Lambert, Paul F et al. (2014) Requirement of estrogen receptor alpha DNA-binding domain for HPV oncogene-induced cervical carcinogenesis in mice. Carcinogenesis 35:489-96|
Showing the most recent 10 out of 358 publications