Dr. Gary Hayward
Herpesvirus Genes and Cell Regulation
Professor of Oncology
Professor of Pathology
Professor of Pharmacology and Molecular Sciences
Ph.D., Otago University, New Zealand
Postdoctoral Fellow, Insititute Gustave-Roussy, Paris, France
University of Chicago and University of Heidelburg, Germany
Pathways of human herpesvirus gene regulation, latency and pathogenesis; enhancer and silencer elements that modulate gene expression; mechanisms of positive and negative transcriptional regulation; interaction with and targeting to subnuclear domains by viral regulatory proteins; molecular piracy and promotion of angiogenesis by Kaposi's sarcoma herpesvirus; virus evasion of interferon-mediated innate immunity; virus evolution and virus hunting.
All human populations harbor latent inapparent infection with many or all of the eight known human herpesviruses. Both acute and chronic herpesvirus infections are particularly serious problems encountered clinically in immunosuppressed cancer and organ transplant patients, as well as in AIDS patients. However, they can also trigger a variety of tumors, lymphoproliferative and angiogenic diseases in immunocompetent patients. The focus of our laboratory research is aimed at understanding how the different classes of herpesviruses usurp control of transcription, DNA replication, cell cycle and other nuclear processes of their host cells and how they also block or evade apoptotic and immune responses in both the lytic and latent state. The large genomes (up to 200 genes) of the three representative herpesviruses that we study encode a series of well defined cascade-like pathways of gene expression that are switched on or off depending on appropriate activated or differentiated states of the host neuronal cells (HSV), myeloid precursor cells (CMV) or vascular endothelial cells (KSHV). Each pathway is driven by complex promoter enhancer domains that control expression of a set of key triggering nuclear IE transactivator proteins. In addition to acting as specific DNA-binding transcription factors that redirect certain cellular factors towards viral transcription, the IE lytic cycle trigger proteins are highly pleomorphic and carry out numerous functions associated with engaging histone acetylase and deacetylase complexes, altering SUMO and ubiquitin modulated cell cycle protein stability and degradation pathways, affecting chromatin structure and RNA nuclear shuttling, replacing components of the cellular DNA synthesis machinery with viral encoded proteins, and blocking both interferon responses and cell cycle progression. In contrast, in the latent state, the viral lytic cycle triggers are repressed, the viral genomes are maintained as episomes and the cells may become immortalized or display "converted" or “transformed” phenotypes. In addition, "captured" cellular genes encoded by KSHV and HCMV, including cytokines, chemokines and chemokine receptors have become modified by a process of "molecular piracy" to play key roles in viral pathogenesis. We also study a novel genus of elephant herpesvirus that cause hemorrhagic disease by infective vascular endothelial cells.
Wu, F.Y., Tang, Q.Q., Chen, H., ApRhys, C., Farrell, C., Chen, J., Fujimuro, M., Lane, M.D., Hayward, G.S. Lytic replication-associated protein (RAP) encoded by Kaposi sarcoma-associated herpesvirus causes p21CIP-1-mediated G1 cell cycle arrest through CCAAT/enhancer-binding protein-alpha. Proc Natl Acad Sci USA 1999.
Hayward, G.S. Initiation of angiogenic Kaposi's sarcoma lesions. Cancer Cell., 3:1-3, 2003.
Yu, Y., Wang, S.E., Hayward, G.S. The KSHV immediate-early transcription factor RTA encodes ubiquitin E3 ligase activity that targets IRF7 for proteosome-mediated degradation. Immunity. 22(1):59-70. 2005.
Hayward, G.S. and Zong, J.-C. Modern evolutionary history of the human KSHV genome. Curr Top Microbiol Immunol. 312:1-42, 2006.
Huh, Y.H., Kim, Y.E., Kim, E.T., Park, J.J., Song, M.J., Zhu, H., Hayward, G.S., Ahn, J.H. Binding STAT2 by the acidic domain of human cytomegalovirus IE1 promotes viral growth and is negatively regulated by SUMO. J Virol. 82(21):10444-54, 2008.
Yu, Y., Hayward, G.S. The ubiquitin E3 ligase RAUL negatively regulates type I interferon through ubiquitination of the transcription factors IRF7 and IRF3. Immunity 33(6):863-77, 2010.
Latimer, E., Zong, J.C., Heaggans, S.Y., Richman, L.K., Hayward, G.S. Detection and evaluation of novel herpesviruses in routine and pathological samples from Asian and African elephants: Identification of two new probosciviruses (EEHV5 and EEHV6) and two new gammaherpesviruses (EGHV3B and EGHV5). Vet Microbiol. 147(1):28-41, 2011.