University of Nebraska - Lincoln
School of Biological Sciences
Nebraska Center for Virology
238 Morrison Center
Lincoln, NE 68583-0900
Phone - 402.472.5905
Fax - 402.472.3323
Publications and Research Interests
Epstein-Barr virus (EBV) is a human herpesvirus of increasing medical importance. EBV infection has been associated with the development of several human cancers. In immunocompromised individuals, such as organ transplant recipients or AIDS patients, EBV almost certainly causes two fatal cancers: post-transplantation lymphoproliferative disorder (PTLD) and AIDS-associated central nerve system (CNS) lymphoma.
Interferon regulatory factors (IRFs) are a small family of transcriptional factors with multiple functions including but not limited to host defense, oncogenesis, apoptosis, viral latency, as well as immune responses.
We were the first to discover the interferon regulatory factor 7 (IRF-7), to identify the first functional interferon stimulated response element (ISRE) in a mammalian viral promoter, and to unearth a novel signal pathway related to IRF-7. In general, the functional importance of IRF-7 is indicated by: (i) IRF-7 and EBV latency have an intimate relation: an EBV latency protein induces the expression of IRF-7, modifies IRF-7 protein by phosphorylation, and relocates IRF-7 protein from the cytoplasm into the nucleus; and (ii) IRF-7 is a primary inducer of interferon (IFN) genes upon viral infection. IFNs are essential factors for the host to control and eliminate viral infection. Thus, IRF-7 holds key information for virus-cell interactions, the understanding of which is an essential step for treatment and preventive measures against viral diseases. Our major interests are to understand the biological roles of IRF-7, and to explore the treatments for EBV-triggered cancers. The research will be a blend of virology, molecular and cellular biology, immunology, and pathology. Major interests are:
1) The functions and regulations of IRF-7 in EBV transformation. EBV transforms human primary B cells in tissue culture and establishes latency. The transformation process offers the best available system to examine the biological roles and regulations of IRF-7. We will take both genetic and biochemical manipulations to identify the target genes of IRF-7 and to dissect the involvement of cellular factors and signaling pathways in the regulation of IRF-7 and their roles in EBV-mediated oncogenesis.
2) The interaction between EBV and HHV8. Human herpesvirus 8 (HHV8) is also called Kaposi's sarcoma-associated herpesvirus (KSHV) because it was first discovered in KS specimens and is believed to be the etiological agent of KS. Interestingly, HHV-8 is implicated in the pathogenesis of AIDS-associated body cavity-based lymphoma (BCBL), and the majority of BCBL cells are also coinfected with EBV. The relationship between the two viruses is under investigation.
3) Potential treatment of human cancers. Currently, there are no effective treatments for EBV-triggered tumors. We are testing a novel approach to specifically block the viral transformation events that lead to the development of human cancers. Our strategy targets an EBV protein that is required for the viral oncogenesis. The method may be developed into a novel cancer therapy.
Selected Recent Publications
1. Jiang, Y., D. Xu, Y. Zhao, and L. Zhang. Mutual Inhibition between Kaposi's Sarcoma-Associated Herpesvirus and Epstein-Barr Virus Lytic Replication Initiators in Dually-Infected Primary Effusion Lymphoma. PLoS One. 3:e1569. 2008.
2. Xu, D., Zhao, L., Del Valle, L., Miklossy, J., and L. Zhang. Interferon regulatory factors 4 is involved in Epstein-Barr virus-mediated transformation of human B lymphocytes. J Virol. 82:6251-8. 2008.
3. Xu, D., J. Zhang, T. Coleman, A. Fagot, C. Kotalik, L. Zhao, P. Trevidi, C. Jones, and L. Zhang. Epstein-Barr Virus Inhibits Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication In Primary Effusion Lymphomas. J. Virol. 81(11):6068-78. 2007.
4. Xu D, K. Brumm, L. Zhang. The latent membrane protein 1 of Epstein-Barr virus primes EBV latency cells for type I interferon production. J Biol Chem. 281: 9163-9169. 2006.
5. Zhang, J., J. Wang, C. Wood, and L. Zhang. KSHV/HHV-8 replication and transcription activator (RTA) regulates both viral and cellular genes via interferon-stimulated response elements. J Virol. 79: 5640-52. 2005.
6. Wang J, J. Zhang, L. Zhang, Harrington W Jr, West JT, Wood C. Modulation of Human Herpesvirus 8/Kaposi's Sarcoma-Associated Herpesvirus Replication and Transcription Activator Transactivation by Interferon Regulatory Factor 7. J Virol. 79:2420-31. 2005.
7. Zhang, J., S. Das, C. Kotalik,, A. Pattnaik, and L. Zhang. The latent membrane protein 1 of Epstein-Barr virus establishes an antiviral state via induction of interferon-stimulated genes. J Biol Chem. 279:46335-46342. 2004c.
8. Zhang, L., J. Zhang, Q. Lambert, C. J. Der, L. Del Valle, J. Miklossy, K. Khalili, Y. Zhou,and J. S. Pagano. Interferon regulatory factor 7 is associated with EBV-transformed CNS lymphoma and has oncogenic properties. J. Virol. 12987-12995. 2004b.
9. Zhang, L. ,K. Hong, J. Zhang, and J. S. Pagano. Multiple signal transducers and activators of transcription (STATs) are induced by EBV LMP-1. Virology. 323:141-152. 2004a.
10. Zhang, L. and J.S. Pagano. Structure and Function of Interferon Regulatory Factor 7. J. Interferon Cytokine Res. 22: 95-101. 2002a.
11. Zhang, L., L. Wu, K. Hong, and J.S. Pagano. Intracellular signaling molecules activated by Epstein Barr virus for induction of interferon regulatory factor 7. J. Virol. 75:12393-401. 2001.
12. Zhang, L. and J.S. Pagano. Interferon Regulatory Factor 7: a Key Cellular Mediator of LMP-1 in EBV Latency and Transformation. Seminars in Cancer Biology 11:445-53. 2001.
University of Kansas Medical Center,
PhD, Biochemistry and Molecular Biology
Shandong Agricultural University,
Assistant Professor, School of Biological Sciences, NE Center for Virology, University of Nebraksa - Lincoln
Research Assistant Professor, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Research Associate, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Postdoctoral Fellow, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
Honors and Special Scientific Recognition:
April, 1995 Recipient of Postdoctoral Fellowship Award by the National Institute of Health
March, 1994 Recipient of Lineberger Fellowship Award by the Lineberger Comprehensive Cancer Center of the University of North Carolina at Chapel Hill.
March, 1993 Honors for Ph.D. dissertation, by the graduate school of the University of Kansas Medical Center at Kansas City