Gary Hayward, Ph.D.
Fax: (410) 955-8685
Interests:
- Herpesvirus Genes and Cell Regulation
Titles
Professor of Oncology
Professor of Pathology
Professor of Pharmacology and Molecular Sciences
Schools/Degrees
Ph.D., Otago University, New Zealand
Training
Postdoctoral Fellow, Insititute Gustave-Roussy, Paris, France
University of Chicago and University of Heidelburg, Germany
Research Summary
Although herpesvirus infections are usually latent and inapparent, they can cause serious human disease and pathogenicity, either as reactivated acute lytic cycle lesions and disseminated viremia, or as neoplasias and tumors driven by viral latent-state oncogenes. Many of these conditions are accelerated by immunosuppression, such as in AIDS and cancer patients and organ transplant recipients.
The overall research goals of the G. Hayward laboratory over the past 30 years have been to define and explain in molecular biological terms how the different types of human herpesviruses cause very different and very specific pathogenicity, with emphasis on how they take genetic control of their host cells, the mechanism they use to trigger oncogenicity, and the switch between latency and the lytic cycle. This includes genetic, biochemical and functional analysis of key viral-encoded regulatory genes that impact on cellular transcription, DNA synthesis, nuclear architecture, cell cycle control, antiviral responses and immune evasion, as well as comparative analysis of gene content and processes, such as cellular gene capture and gene piracy as key events in the evolutionary origin and divergence of the several different subfamilies of human and primate herpesviruses. The current research goals of this group centers on the biological process in which Kaposi’s sarcoma-associated herpesvirus (KSHV) converts normal metabolic vascular endothelial cells into proliferating pro-angiogenic spindloid tumor cells; the mechanism used by two KSHV immediate-early lytic cycle nuclear transcription factors (RTA and RAP) to cause cell cycle arrest via transcriptional activation and stabilization of C/EBPá, cJUN, pRB and p21; and the direct and indirect mechanisms used by the KSHV immediate-early nuclear transcription factor RTA acting as an intrinsic UbE3ligase to block cellular interferon responses by degrading IRF7 and IRF3 as well as to counteract pro-latency effects during reactivation.
We are also interested in herpesvirus genomic evolution including determining the modern evolutionary history of the KSHV and HCMV genomes in different human populations, especially the significance of subtype clustering and allelic chimerism involving multiple highly diverged versions of several key viral genes. In addition, we are working to understand the roles of two cytomegalovirus (CMV) immediate-early nuclear regulatory proteins (IE1 and IE2) that control the initiation and progression of the lytic cycle. In particular, current focus is targeted at how they interact with and alter cellular subnuclear bodies containing the PML tumor suppressor that play roles in regulation of SUMO modification, cell cycle control and transcriptional repression. Finally, we have discovered a novel genus of endotheliotrophic mammalian herpesviruses that cause devastating acute hemorrhagic disease in elephants and are using the sensitive PCR methodology involved in identifying those viruses for developing novel new virus-hunting approaches.
Journal Citations
Alcendor, DJ., Zong, J-C., Dolan, A., Gatherer, D., Davison, AJ. and Hayward, GS. (2009) Patterns of Divergence in the vCXCL and vGPCR Gene Clusters in Primate Cytomegalovirus Genomes. Virology. 395:21-32.
Garner, M.M., Helmick, K., Ochsenreiter, J., Richman, L.K., Latimer, E., Wise, A.G., Maes, R.K., Kiupel, M., Nordhausen, R.W., Zong, J.C., and Hayward, G.S. (2009). Clinico-pathologic features of fatal disease attributed to new variants of endotheliotropic herpesviruses in two Asian elephants (Elephas maximus). Vet Pathol 46, 97-104.
Huh, Y.H., Kim, Y.E., Kim, E.T., Park, J.J., Song, M.J., Zhu, H., Hayward, G.S., and Ahn, J.H. (2008). Binding STAT2 by the acidic domain of human cytomegalovirus IE1 promotes viral growth and is negatively regulated by SUMO. J Virol 82, 10444-10454.
Arav-Boger, R., Battaglia, C. A., Lazzarotto, T., Gabrielli, L., Zong, J. C., Hayward, G. S., Diener-West, M. & Landini, M. P. (2006). Cytomegalovirus (CMV)-encoded UL144 (truncated tumor necrosis factor receptor) and outcome of congenital CMV infection. J Infect Dis 194, 464-73.
Hayward, G. S., and J. C. Zong. 2007. Modern evolutionary history of the human KSHV genome. Curr Top Microbiol Immunol 312:1-42.
Zong, J. C., R. Arav-Boger, D. J. Alcendor, and G. S. Hayward. 2007. Reflections on the interpretation of heterogeneity and strain differences based on very limited PCR sequence data from Kaposi's sarcoma-associated herpesvirus genomes. J Clin Virol 40:1-8.
Zong, J. C., H. Kajumbula, W. Boto, and G. S. Hayward. 2007. Evaluation of global clustering patterns and strain variation over an extended ORF26 gene locus from Kaposi's sarcoma herpesvirus. J Clin Virol 40:19-25.
Huang, J., Liao, G., Chen, H., Wu, F. Y., Hutt-Fletcher, L., Hayward, G. S. & Hayward, S. D. (2006). Contribution of C/EBP proteins to Epstein-Barr virus lytic gene expression and replication in epithelial cells. J Virol 80, 1098-109.
Kajumbula, H., Wallace, R. G., Zong, J. C., Hokello, J., Sussman, N., Simms, S., Rockwell, R. F., Pozos, R., Hayward, G. S. & Boto, W. (2006). Ugandan Kaposi's sarcoma-associated herpesvirus phylogeny: evidence for cross-ethnic transmission of viral subtypes. Intervirology 49, 133-43.
Yu, Y.X., Wang, S.E., Hayward,G.S. (2005). The KSHV Immediate-Early Transcription Factor RTA Encodes Ubiquitin E3 Ligase Activity that Targets IRF7 for Proteosome-Mediated Degradation. Immunity. 22: 59–70.
Lee, H. R., Kim, D. J., Lee, J. M., Choi, C. Y., Ahn, B. Y., Hayward, G. S., et al. 2004. Ability of the human cytomegalovirus IE1 protein to modulate sumoylation of PML correlates with its functional activities in transcriptional regulation and infectivity in cultured fibroblast cells. J. Virol. 78:6527-6542.
Wang, S. E., Wu, F. Y., Chen, H. L., Shamay, M., Zheng, Q. Z., & Hayward, G. S. 2004. Early activation of the Kaposi’s sarcoma-associated herpesvirus (KSHV) RTA, RAP and MTA promoters by the TPA-induced AP1 pathway. J. Virol. 78:4248-4267.
Wang, S. E., Wu, F. Y., Yu, Y. X., & Hayward, G. S. 2003. CCAAT/enhancer-binding protein-á is induced during the early stages of Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic cycle reactivation and together with the KSHV replication and transcription activator (RTA) cooperatively stimulates the viral RTA, MTA and PAN promoters. J. Virol. 77:9590-9612.
Wu, F. Y., Chen, H. L., Wang, S. E., ApRhys, C. M., Liao, G., Fujimuro, M., et al. 2003. CCAAT/enhancer binding protein alpha interacts with ZTA and mediates ZTA-induced p21 (CIP-1) cell cycle arrest during the Epstein-Barr virus lytic cycle. J. Virol. 77:1481-1500.
Wu, F. Y., Wang, S. E., Tang, Q. Q., Fujimuro, M., Chiou, C. J., Zheng, Q., et al. 2003. Cell cycle arrest by Kaposi’s sarcoma-associated herpesvirus replication associated protein is mediated at both the transcriptional and posttranslational levels by binding to CCAAT/enhancer-binding protein-á and p21CIP-1. J. Virol. 77:8893-8914.
