 | Eshuang@med.unc.edu
32-006 Lineberger Comprehensive Cancer Center
Campus Box 7295
Chapel Hill, NC 27599-7295
919.966.4323 or 2062 |
Research
Human cytomegalovirus (HCMV) is a ubiquitous and highly sero-prevalent pathogen that causes significant morbidity and mortality in immunocompromised individuals and patients with cancer and AIDS. This virus is a leading cause of birth defects and has been associated with coronary restenosis, atherosclerosis, and inflammatory bowel diseases.
Our research interest is to understand the molecular biology, pathogenesis and possible oncogenicity of HCMV. Current research projects can be categorized into four areas: viral ligands and cellular receptor(s), HCMV and human malignancy, HCMV disruption of endothelial cell functions, and the search for anti-CMV Compounds.
(A). Viral ligands and Cellular Receptor(s).
This study focuses on the identification of viral envelope proteins and cellular receptor(s) that play important roles in viral entry and virus-induced cellular signaling. We employ cross-linking, gene transfection, protein displacement, and gene cloning and expression of HCMV-specific membrane proteins, such as glycoproteins gB and gH, to identify cellular receptor and co-receptor for HCMV infection.
(B). HCMV and Human Malignancy.
This study investigates the possible causal association between HCMV and human malignancies. We investigate the interaction between the HCMV immediate-early (IE) proteins and cell cycle regulatory proteins, such as cyclins, E2F, p53 and pRb-related proteins, which may disrupt cell cycle regulation leading to abnormal cell growth. Our studies include the study on the mechanisms by which HCMV initiates signaling events following HCMV infection and the interactions between viral IE proteins and cell cycle proteins. We found that the engagement of viral gB ligand with cell surface receptor(s) is sufficient to activate cellular transcription factors Sp1 and NF-kB, indicating that the HCMV glycoprotein(s) mediate an initial level of signaling to prime the cell for viral replication. Additionally, our data shows that the IE1-72 protein binds and functionally inactivates the cellular p107 protein presumably creating an S-phase like environment to facilitate viral DNA replication.
(C). HCMV Disruption of Endothelial Cell Functions.
This study investigates the relationship between the status of EGF receptor (EGFR) and integrin avb3 on the endothelial cell surface and cell's susceptibility to HCMV infection, and the consequence of subsequent viral gene expression, particularly IE1-72 and IE2-86 proteins, on endothelial cell proliferation.
(D). The search of potential Anti-CMV Compounds.
This study involves the search for potent anti-CMV compounds by targeting on: (a) viral entry: determining the interacting domains between HCMV gB and EGFR for designing molecule(s) that can block viral entry at first step of viral infection, (b) virus-induced signaling pathways: the search of anti-virus compounds that block EGFR kinase and MAPK activities, and (c) viral and cellular enzymes which are essential for HCMV replication: the cellular topoisomerase II, the virus-specified DNA polymerase and the viral protease (UL80) are used as targets.
Publications
Johnson, R.A., S.-M. Huong, and E.-S. Huang. 2000. Activation of the mitogen activated protein kinase (MAPK) p38 by HCMV infection through two distinct pathways: A novel mechanism of activation of p38. J.Virol. 74: 1158-1167.
Johnson, R.A., X.-L. Ma, A. D. Yurochko, and E.-S. Huang. 2001. The Role of MKK1/2 kinase activity in human cytomegalovirus infection. J. Gen. Virology, 82: 493-497.
Johnson, R. A., X. Wang, X.-L. Ma., S.-M. Huong, E.-S. Huang, 2001, Human cytomegalovirus up-regulates the phosphatidylinositol 3-kinase pathway: Inhibition of PI3-K activity inhibits viral replication and viral-induced signaling. J. Virology 75. 6022-6032.
Andreoni, K. A., X. Wang, S.-M. Huong, and E.-S. Huang. 2002. CytoGam neutralizes HCMV infectivity and inhibits HCMV-induced intracellular NF-kB, Sp1, and PI-K signaling pathways. J. Med. Virol. 67: 33-40.
Efferth, T., M. Marshchall, X. Wang, S.-M. Huong, I. Hauber, A. Olbrich, T. Stamminger, and E.-S. Huang. 2002. Antiviral activity of artesunate towards wild type, recombinant and ganciclovir-resistant human cytomegalovirus. J. Mol. Medicine, 80: 233-242.
Wang, X., S.-M. Huong, M. L. Chiu, N. Raab-Traub, and E.-S. Huang. 2003. EGF receptor is a cellular receptor for human cytomegalovirus. Nature, 424: 456-461.
Zhang, Z., S.-M. Huong, X. Wang, D.Y. Huang, and E.-S. Huang. 2003. Interactions between human cytomegalovirus IE1-72 and Cellular p107: Functional domains and mechanisms of the up-regulation of cyclin E/cdk2 kinase activity. J. Virology. 77:12660-12670.
Evers, D.L., X. Wang, S.-M. Huong, D.Y. Huang and E.-S. Huang. 2004. 3,4’,5-trihydroxy-trans-stilbene (resveratrol) inhibits human cytomegalovirus replication and virus-induced cellular signaling. Antiviral Research, 63:85-95.
Evers D.L. X. Wang, and E.-S. Huang. 2004. Cellular stress and signaling response to human cytomegalovirus infection. Microbes and Infection. 6:1084-1093.
Evers, D.L., X. Wang, S.-M. Huang, K.A. Andreoni, E.-S. Huang. 2005. Inhibition of human cytomegalovirus signaling and replication by the immunosuppresant FK778. Antiviral Research 65: 1-12.
Wang, X., D. Y. Huang, S.-M. Huong and E.-S. Huang. 2005. Integrin avb3 is a coreceptor for human cytomegalovirus. Nature Medicine, 11: 515-521.
Evers, D.L., C.-F. Chao, X. Wang,, Z. Zhang, S.-M. Huong, E.-S. Huang. 2005. Human cytomegalovirus-inhibitory flavonoids: Studies on antiviral activity and mechanism of action. Antiviral Research 68: 124-134.
Zhang Z., E. L. Evers, J. F. McCarville, J.-C, Dantonel, S.-M. Huong, and E.-S. Huang. 2005. Evidence that the human cytomegalovirus IE2-86 protein binds mdm2 and facilitates mdm2 degradation. J. Virol. (In revision).
Click here for a list of publications
Accomplishments
During the past five years, we have made following accomplishments in our research:
(a). We have determined that human cytomegalovirus gB and gH membrane glycoproteins are a group of potent mitogens that can initiate the rapid activation of transcription factors NF-kB and Sp1.
(b). We discovered that HCMV IE1-72 protein can bind to cellular p107 (pRb-related pocket protein) and alleviated p107-mediated transcriptional repression of E2F-mediated gene expression and cyclin E/cdk2 dependent cell growth.
(c). We found that the EGF receptor is a cellular receptor for HCMV. This discovery impacts our understanding of mechanism of viral entry and the development of antiviral agents. We have also recently identified that HCMV uses Integrin avb3 as a coreceptor for viral entry and signaling.
(d). We observed that HCMV infection activates PI3-K signaling pathway, MAPK (p38 and ERK1/2), and EGFR kinase. Disruption of these signaling pathways blocks normal HCMV replication.
(e). We have recently identified the following potent anti-HCMV compounds: three isoflavone derivatives, one stilbene derivative, one destuxin derivative, and the immunosuppressant FK778.
Affiliations
Division of Infectious Diseases, Department of Medicine, UNC-Chapel Hill
Member, the Lineberger Comprehensive Cancer Center, UNC-Chapel Hill
Department of Microbiology and Immunology
