Dr. John Nicholas
Molecular biology of oncogenic herpesviruses, mechanisms of viral pathogenesis, signal transduction by viral cytokines and chemokine receptors. Properties and Roles of Viral Cytokines in HHV-8 Related Malignancies
Professor of Oncology
Joint Appointment in Molecular Microbiology and Immunology
Ph.D., National Institute for Medical Research, London, U.K.
Fellow, Molecular Virology, Duke University, Durham, NC
Fellow, Molecular Virology, National Institute of Medical Research
Research in this laboratory is directed toward understanding the relevance of captured cellular gene homologues to replication and pathogenesis of human herpesvirus-8 (HHV-8), an oncogenic virus associated with endothelial tumor Kaposi’s sarcoma (KS) and B cell malignancies primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD). Like other herpesviruses, HHV-8 is able to undergo lytic replication to produce new infectious particles and also to establish latent infections, which for some gamma (lymphotropic) herpesviruses can lead to neoplasia. HHV-8 specifies a homologue of interleukin-6 (vIL-6), three chemokine homologues (vCCL-1, vCCL-2, vCCL-3), and a chemokine receptor-related G protein-coupled receptor (vGPCR) that have been implicated as contributors to HHV-8-associated neoplasia because of their angiogenic, proliferative and anti-apoptotic activities. The virus encodes several other cellular homologues, including four viral interferon regulatory factors (vIRFs 1-4), which function to evade innate cellular defenses against virus infection by inhibiting host IRF functions and via other mechanisms.
Research projects currently being undertaken in this laboratory are aimed at addressing: (1) the mechanisms by which vIL-6 is retained largely intracellularly, in the endoplasmic reticulum (ER), and is able to signal from this compartment; (2) the signal transduction pathways and downstream targets mediating anti-apoptotic signaling by the viral chemokines in PEL and endothelial cells; (3) the mechanistic basis of vGPCR-mediated survival signaling in PEL and endothelial cells; (4) the roles of the v-cytokines and vGPCR in virus replication; (5) the molecular mechanisms by which vIRF-1 associates with pro-apoptotic Bcl-2 family members to inhibit their activities, directly and via their nuclear sequestration, and the relevance of such activity to virus biology and viral pathogenesis. The overall goal of this research is to define the mechanisms of action and importance to viral replication of these proteins to allow assessment of their suitability as therapeutic targets and development of reagents to specifically block their activities.
Choi Y.B., and J. Nicholas. 2008. Human herpesvirus 8 viral chemokines vCCL-1 and vCCL-2 signal through CCR8 in endothelial cells to enhance cell survival and productive virus replication via autocrine and paracrine mechanisms. J Virol. 82:6501-6513.
Chen D., G. Sandford, and J. Nicholas. 2009. Intracellular signaling mechanisms and activities of human herpesvirus 8 interleukin-6. J Virol. 83:722-733.
Chen D., Y.B. Choi, G. Sandford, and J. Nicholas. 2009. Determinants of secretion and intracellular localization of human herpesvirus 8 interleukin-6. J Virol. 83:6874-6882.
Sandford G., Y.B. Choi, and J. Nicholas. 2009. Role of ORF74-encoded viral G protein-coupled receptor in human herpesvirus 8 lytic replication. J Virol. 83:13009-13014.
Choi, Y.B., and J. Nicholas. 2010. Bim nuclear translocation and inactivation by viral interferon regulatory factor. PLoS Pathogens 6:e1001031.