Bernard Roizman, Sc.D.

Herpes Simplex Virus Genome Structure, Gene Expression, Viral Latency

Research Summary

Herpes simplex viruses are large DNA pathogens encoding at least 84 proteins. Our research focuses on the molecular biology of these viruses and in particular on two areas: The first concerns the mechanisms by which the virus subjugates the infected cell, evades host responses, and makes the cell produce many thousands of virus particles. Current studies center on the functions of several proteins (i) a multifunctional protein designated ICP0 that block the silencing of the viral DNA on entry into cells and acts as a ubiquitin ligase that targets cellular proteins potentially inimical to the virus (ii) a protein designated UL41 that selectively degrades mRNA to block host responses to infection, (iii) a viral protein kinase known as US3 that blocks programmed cell death induced by viral gene products, cellular factors or exogenous agents, and (iv), a viral protein known as ICP22 that scavenges the infected cell for a cellular protein that it uses to enhance viral protein synthesis. The second area of research is based on the accumulated knowledge regarding viral gene functions and the ability to genetically engineer novel viruses. Our objective is to make novel viruses that specifically target cancer cells and selectively destroy them without affecting normal cells. These studies have generated highly promising results and may lead to the transformation of a human pathogen into a therapeutic agent.

Selected Papers

Taddeo, B., Zhang, W., Lakeman, F., and Roizman, B. (2004). Cells lacking NF-kB or in which NF-kB is not activated vary with respect to ability to sustain herpes simplex virus 1 replication and are not susceptible to apoptosis induced by a replication incompetent virus. J. Virol. 78:11615-11621.

Escaltine, A., Taddeo, B. and Roizman, B. (2004). The U_L41 protein of herpes simplex virus mediates selective degradation of cellular mRNAs. Proc. Nat. Acad. Sci. (USA ) 101:18165-18170.

Zhou, G. and Roizman, B.  (2005). Characterization of a recombinant herpes simplex virus 1 targeted to enter cells via the IL13Ra2 receptor of malignant glioma cells. J. Virol.79:5272-5277.

Durand, L.O, Advani, S.J. and Roizman, B. (2005). The carboxyl-terminal domain of RNA POL II is phosphorylated by a complex containing cdk9 and the infected-cell protein No. 22 of herpes simplex virus 1. J. Virol, 79:6757-6762.

Poon, A.P.W. and Roizman, B. (2005). The herpes simplex virus 1 ICP22 regulates the accumulation of a shorter mRNA and of a truncated U_S3 protein kinase that exhibits altered functions. J. Virol. 79:8470-8479.

Liang, Y., Kurakin, A., and Roizman, B. (2005). Herpes simplex virus 1 ICP0 forms a complex with CIN85 and Cbl and mediates the degradation of EGFR from cell surfaces. Proc. Nat. Acad. Sci (USA) 5838-5843.

Gu., H., Liang, Y., Mandel, G. and Roizman, B. (2005). Components of the REST/CoREST/HDAC repressor are disrupted, modified and translocated in herpes simplex virus 1 infected cells. Proc. Nat. Acad. Sci. (USA) 102:5771-7576.

Roizman, B., Gu, H, and Mandel, G. (2005). The frst 30 minutes in the life of a virus:  unREST in the nucles.  Cell Cycle 4:1019-1021.

Mezhir, J.J., Advani, S.J., Smith, K.D., Darga, T.E., Poon, A.P.W., Schmidt, H., Posner, M.C., Roizman, B., an Weichselbaum, R.R.  (2005). Ionizing radiation activates late herpes simplex virus 1 promoters via the p38 pathway in tumors treated with oncolytic viruses.  Cancer Research 65:9479-9484.

Hellums, E.K., Market, J.M., Parker, J.N., He, B., Perbal, B., Roizman, B., Whitley, R.J., Langford, C.P., Bharara, S., and Gillespie, G.Y.  (2005).  Increased efficacy of an interleukin-12-secreting herpes simplex virus in a syngeneic intracranial murine glioma model. Neuro-Oncology 7?213-224.

Kamiyama, H., Zhou, G., and Roizman, B. (2006). Herpes simplex virus 1 recombinant virions exhibiting the amino terminal fragment of urokinase-type plasminogen activator can enter cells via the cognate receptor.  Gene Ther. 13:621-629.

Smith, K.D., Mezhir, J.J., Bickenbach, K., Veerapong, J., Charron, J., Posner, M.C., Roizman, B., and Weichselbaum, R.R. (2006). Activated MEK suppresses activation of PKR and enables efficientreplication and in vivo oncolysis by ₁34.5- mutants of herpes simplex virus 1. J. Virol. 80:1110-1120.

Taddeo, B., Zhang, W., and Roizman, B. (2006). The U_L41 protein of herpes simplex virus 1 degrades RNA by endonucleolytic cleavage in absence of other cellular or viral proteins. Proc Nat Acad Sci (USA) 103:2827-2832.

Benetti, L. and Roizman, B. (2006). Protein kinase B/Akt is present in activated form throughout the entire replicative cycle of U_S3 mutant virus but only at early times after infection with wild-type herpes simplex virus 1. J. Virol. 80:3341-3348.

Liang, Y and Roizman, B. (2006). The state and role of Src family kinases in the replication of herpes simplex virus 1. J. Virol. 80:3349-3359.

Poon, A.P.W., Benetti, L., and Roizman, B. (2006). U_S3 and U_S3.5 protein kinases of herpes simplex virus 1 differ with respect to their functions in blocking apoptosis and in virion maturation and egress.  J. Virol. 80:3752-3764.

Zhou, G., and Roizman, B. (2006). Construction and properties of a herpes simplex virus 1 designed to enter cells solely via the ILI32 receptor. Proc Nat Acad Sci 103:5508-5513.

Campadelli-Fiume, G., and Roizman, B. (2006). The egress of herpesviruses from cells: the unanswered questions. Letter to the Editor. J Virol 80:6716-6719.

Liang, L., and Roizman, B. (2006). Herpes simplex virus 1 precludes replenishment of the short-lived receptor of tumor necrosis factor alpha by virion host shutoff-dependent degradation of its mRNA. J Virol 80:7756-7759.

Poon, A.P.W., Gu, H., and Roizman, B. (2006). ICPO and US3 protein kinase of herpes simplex virus 1 independently block histone and deacetylation to enable gene expression. Proc Nat Acad Sci (USA) 103:9993-9998.

Taddeo, B., and Roizman, B. (2006). The virion host shutoff (U_L41) protein of herpes simplex virus 1 is an endoribonuclease with a substrate specificity similar to that of RNase A. J Virol 80:9341-9345.

Roizman, B., and Taddeo, B. (2006). HSV-1 and the Host Cell: a story of global conspiracies, plots and counterplots. Alpha Herpesviruses; Molecular and Cellular Biology. R. Sandhi-Golidin Ed. Horizon Scientific Press, pp261-282.

Advani, S., Mezhir, J.J., Roizman, B., and Weichselbaum, R.R. (2006). ReVOLT: Radiation Enhanced Viral Oncolytic Therapy. Int J Radiation Oncology Biol Phys 66:637-646.

Roizman, B. and Campadelli-Fiume, G. (2006). Herpes simplex virus. Fundamentals of Molecular Virology. N.H. Acheson Ed. Wiley, pp134-146.

Baines, J.D., Wills, E., Jacob, R.J., Pennington, J. and Roizman B. (2007). Glycoprotein M of herpes simplex virus 1 is incorporated into virions during budding at the inner nuclear membrane. J Virol 81:800-812.

Pellet, P.E. and Roizman, B. (2007). The Family Herpesviridae: A brief introduction. Fields' Virology 5th Edition. D.M. Knipe, P. Howley, D.E. Griffin, R.A. Lamb, M.A. Martin, B. Roizman, and S.E. Straus, Editors. Lippincott-Williams and Wilkins, New York, N.Y., pp2479-2499.

Roizman B., Knipe, D.M. and Whitley, R.J. (2007). The replication of Herpes simplex viruses. Fields' Virology 5th Edition. D.M. Knipe, P. Howley, D.E. Griffin, R.A. Lamb, M.A. Martin, B. Roizman and S.E. Straus, Editors. Lippincott-Williams and Wilkins, New York, N.Y. pp2501-2601.

Poon, A.P.W. and Roizman, B. (2007). Separation of receptor binding and pro-fusogenic domains of glycoprotein D of herpes simplex virus 1 into distinct interacting proteins. Proc Nat Acad Sci (USA) 104:4142-4146.

Kalamvoki, M. and Roizman, B. (2007). Bcl-2 blocks accretion or depletion of stored calcium, but has no effect on the redistribution of the IP3-1 receptor mediated by glycoprotein E of herpes simplex virus 1. J Virol 81:6316-6325.

Kari, I., Syrjänen, S., Johansson, B., Peri, P., He, B., Roizman, B. and Hukkanen, V. (2007). Antisense RNA Directed to the Human Papillomavirus Type 16 E7 mRNA from Herpes Simplex Virus Type 1 Derived Vectors is Expressed in CaSki Cells and Downregulates E7 mRNA. J Virol 4:47-58.

Roizman, B. and Campadelli-Fiume, G. (2007). Viral genes and their function. Human Herpesviruses: Biology, Therapy and Immunoprophylaxis. Arvin, A.M., Campadelli-Fiume, G., Mocarski, E., Moore, P.S., Roizman, B., Whitley, R.J. and Yamanishi, K, Editors. Cambridge Univ Press, pp70-92.

Roizman, B. and Taddeo, B. (2007). The strategy of viral replication and takeover of the host cell. Human Herpesviruses: Biology, Therapy and Immunoprophylaxis. Arvin, A.M., Campadelli-Fiume, G., Mocarski, E., Moore, P.S., Roizman, B., Whitley, R.J. and Yamanishi, K., Editors. Cambridge Univ Press, pp163-173.

Taddeo, B., Sciortino, M.T., Zhang, W. and Roizman, B. (2007). Interaction of herpes simplex virus RNase with VP16 and VP22 is required for the accumulation of the protein but not for accumulation of mRNA. Proc Nat Acad Sci USA 104:12163-12168.

Skelly, C.L., Amito Chandiwal, A., Vocisky, J.F., Ralph, R., Weichselbaum, R.R. and Roizman, B. (2007). Attenuated herpes simplex virus 1 blocks arterial apoptosis and intimal hyperplasia induced by balloon angioplasty and reduced blood flow. Proc Nat Acad Sci 104:12474-12478.

Benetti, L. and Roizman, B. (2007). In transduced cells, the US3 protein kinase of herpes simplex 1 precludes activation and induction of apoptosis by transfected procaspase 3. J Virol 81:10242-10248.

Veerapong, J., Bickenbach, K.A., Shao, M., Smith, K.D., Posner, M.C., Roizman, B. and Weichselbaum, R.R. (2007). Systemic delivery of ₁34.5-deleted herpes simplex virus 1 selectively targets and treat distant human xenograft tumors that express high MEK activity. Cancer Res 67:8301-8306.

Sciortino, M.T., Taddeo, B., Giuffrè-Cuculletto, M., Medici, M.A., Mastino, A. and Roizman, B. (2007). Replication competent herpes simplex virus 1 isolates selected from cells transfected with a BAC-DNA lacking solely the U_L49 gene vary with respect to the defect in the U_L41 gene encoding the host shutoff RNase. J Virol 81:10924-10932.

Khodarev, N.N., Minn, A.J., Efimova, E.V., Darga, T.E., Labay, E., Beckett, M., Mauceri, H., Roizman, B. and Weichselbaum, R.R. (2007). Signal transducer and activator of transcription 1 regulates both cytotoxic and prosurvival functions in tumor cells. Cancer Research 67:9217-9220.

Gu, H. and Roizman, B. (2007). Herpes simplex virus ICP0 blocks the silencing of viral DNA by dissociating HDACs from the CoREST/REST complex. Proc Nat Acad Sci (USA) 104:17174-17139.

Yang, K., Poon, A.P.W., Roizman, B. and Baines, J.D. (2008). Temperature-sensitive mutations in the putative herpes simplex virus 1 terminase subunits U_L15 and U_L33 preclude viral DNA cleavage/packaging and interaction with pU_L28 at the nonpermissive temperature. J Virol 82:487-494.

Kalamvoki, M., Qu, J. and Roizman, B. (2008). Translocation and colocalization of ICP4 and ICP0 in cells infected with herpes simplex virus 1 mutants lacking glycoprotein E, glycoprotein I or the virion host shutoff product of U_L41 gene. J Virol 82:1701-1713.

Jovasevic, V., Liang, L. and Roizman, B. (2008). Proteolytic cleavage of VO1-2 is required for the release of herpes simplex virus 1 DNA into the nucleus. J Virol 82:2211-2219.

Smith-Donald, B.A., Durand, L.O. and Roizman, B. (2008). The role of cellular phosphatase cdc25C in herpes simplex virus 1 replication. J Virol 82:4527-4532.

Smith-Donald, B.A., and Roizman, B. (2008). The interaction of herpes simplex virus 1 regulator protein ICP22 with the cdc25C phosphatase is enabled in vitro by viral protein kinases U_S3 and U_L13. J Virol 82:4533-4543.

Liang, L. and Roizman, B. (2008). The expression of interferon y dependent genes is blocked independently by the virion host shutoff RNase and by the U_S3 protein kinase. J Virol 82:4688-4696.