Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

THE PELLETTLABORATORYRESEARCH ASSOCIATEFu-Zhang Wang, Ph.D.POSTDOCTORAL FELLOWSSubhendu Das, Ph.D.Olena Skomorovska-Prokvolit, Ph.D.SENIOR RESEARCHTECHNOLOGISTGeorge CompitelloCOLLABORATORSVIROLOGYRobin Avery, M.D. 1Belinda Yen-Liberman, Ph.D. 21Dept. of Infectious Diseases,CCF2Dept. of Pathology andLaboratory Medicine, CCFHerpesviruses: Molecular Marvelsand Potent PathogensHerpesviruses constitute a virus family ofgreat genetic and biologic diversity. Theherpesviruses that infect humans includeherpes simplex virus types 1 and 2 (whichpredominantly cause oral and genital disease,respectively), the virus that causes chicken poxand shingles (varicella-zoster virus), most casesof infectious mononucleosis (Epstein-Barrvirus), roseola infantum (Human herpesvirus 6B),and Kaposi’s sarcoma (Kaposi’s sarcomaassociatedherpesvirus, a.k.a. Human herpesvirus8). Of the human herpesviruses,the one with perhapsthe greatest clinical impact ishuman cytomegalovirus,which is a leading cause ofcongenitally acquired mentalretardation and deafness,causes some infectiousmononucleosis, is a majorpathogen in immunocompromisedpatients, and mayhave a role in the developmentof atherosclerosis andother occlusive vasculardiseases. An importantshared biologic property ofall herpesviruses is latency,the process by which theseviruses persist in their host ina generally quiescent mannerfor the life of the host. Inimmunocompromised hosts,such as organ transplant recipients who havebeen chemically immunosuppressed to preventrejection of the transplanted organ, theseformerly quiescent viruses can each emerge fromlatency and cause significant disease that is oftendifficult to treat.The genetic complexity and diversity ofCannon, M.J., Dollard, S.C., Smith, D.K., Klein, R.S., Schuman, P., Rich, J.D., Vlahov,D., Pellett, P.E. for the HIV Epidemiology Research Study Group (2001) Blood-borne andsexual transmission of human herpesvirus 8 in women with or at risk for human immunodeficiencyvirus infection. N. Engl. J. Med. 344:637-643.Krug, L.T., Inoue, N., and P.E. Pellett (2001) Sequence requirements for interaction of humanherpesvirus 7 origin binding protein with the origin of lytic replication. J. Virol. 75:3925-3936.Cannon, M.J., Dollard, S.C., Black, J.B., Edlin, B.R., Hannah, C., Hogan, S.E., Patel,M.M., Jaffe, H.W., Offermann, M.K., Spira, T.J., Pellett, P.E., and C.J. Gunthel (2003)Risk factors for Kaposi’s sarcoma in men seropositive for both Human herpesvirus 8 andhuman immunodeficiency virus. AIDS 17:215-222.Stover, C.T., Smith, D.K., Schmid, D.S., Pellett, P.E., Stewart, J.A., Klein, R.S., Mayer,K., Vlahov, D., Schuman, , P. and M.J. Cannon, for the HIV Epidemiology ResearchStudy Group (2003) Prevalence of and risk factors for viral infections among HIV-infectedand high-risk-uninfected women. J. Infect. Dis. 187:1388-1396.Cannon, M.J., Laney, A.S., and P.E. Pellett (2003) Human herpesvirus 8: current issues.Clin. Infect. Dis. 37:82-87.The Department of Molecular BiologyPhilip E. Pellett, Ph.D.herpesviruses, coupled with their complex hostbiology, make these viruses engaging objects ofscientific study, providing fascinating and importantintersections with almost every area ofmolecular biology, cellular biology, immunology,pathogenesis, and epidemiology.The purposes of this laboratory (establishedin 2003) are (i) to conduct basic researchthat adds to our fundamental understanding ofthe relationships among the various herpesviruses,the processes by which human herpesvirusesreplicate and persist inpopulations on an evolutionarytime scale, and themechanisms by which theseviruses cause disease, and (ii)to use this knowledge toprevent or treat herpesvirusassociateddisease.Initiation of HerpesvirusDNA ReplicationOur studies ofherpesvirus replicationinclude structure-functionanalysis of the origin-bindingprotein (OBP), a protein thatis con-served among manymembers of the herpesvirusfamily. OBP binds to theorigin of lytic replication andserves as a nucleatingscaffold for assem-bly of thereplication fork and as an active parti-cipant inpreparing the origin sequence for repli-cationinitiation. We have mapped the structuraldomains responsible for the sequence-specificDNA binding activity of OBP, defined sequencesit can bind to, and found that the protein interactswith one face of the DNA double helix. In subsequentwork, we will identify important conservedfeatures of the structure of the proteinand identify means by which the protein-DNAinteraction can be blocked, so as to inhibit viralreplication.Human Cytomegalovirus Molecular andCellular BiologyWe are initiating a research programdirected at understanding the role of humancytomegalovirus in disease processes, such asinflammation and immune diversion, and themanner in which certain virally encoded proteinsand viral genetic variation contribute to this.Herpesvirus Translational ResearchThe translational research component of ourprogram is directed at improving patient out-comeswith respect to herpesvirus-related disease. Thiseffort will involve a multidisciplinary collaborationbetween basic laboratory scientists, clinical virologists,infectious and vascular disease specialists,epidemiologists, and biostatisticians.114