William S. M. Wold, Ph.D.
William S.M. Wold, Ph.D.
Human adenoviruses commonly cause acute infections of the respiratory and GI tracts, the eye, and various other tissues. They also form long-term persistent infections, and their emergence is a major problem in immunocompromised patients. Recently, there has been a great deal of interest in using adenoviruses as genetically-engineered “vectors” for specialized vaccines, for gene therapy, and for cancer gene therapy (adenovirus as a drug to treat cancer).
Adenoviruses are one of the premier model systems to study the molecular and cellular biology of human cells. Adenoviruses have a DNA genome, they transform cultured cells to a malignant state, and they can induce tumors in experimental animals (but not in humans). Thus, adenoviruses are excellent models to understand cancer. Adenovirus genes are expressed in the cell nucleus using primarily host cell mechanisms, and many of the adenovirus gene products usurp key regulatory aspects of the cell to facilitate replication. Many fundamental discoveries have been made using adenoviruses.
I have studied the molecular aspects of human adenovirus replication for four decades. Much of our early research focused on the seven protein products of the E3 transcription unit. We were the first to identify six of the seven E3 proteins, and we and our collaborators were the first to determine the function of the E3-14.7K, E3-RIDα, E3-RIDβ, and Adenovirus Death Protein proteins (Fig. 1). In general, the E3 proteins function to protect adenovirus-infected cells from destruction by host immune killer cells.
Fig. 1.Adenovirus proteins in the E3 transcription unit that counteract killing of adnovirus-infected cells by cells of the host immune system.
One of the E3 proteins we discovered and characterized is named the “Adenovirus Death Protein” (ADP). ADP functions at the culmination of infection to facilitate lysis of the infected cell and the release of progeny adenovirus from the cell. Based on the function of ADP, we developed oncolytic adenovirus vectors for cancer gene therapy. Oncolytic adenovirus vectors destroy cancer cells through the natural process of virus replication (Fig. 2). We hypothesized that if adenovirus could be engineered to “overexpress” ADP (as compared to wild type adenovirus), then the adenovirus vector would have enhanced ability to lyse cancer cells and to spread from cell to cell in the tumor, thereby destroying the tumor. This approach proved to be successful: our ADP-overexpressing vector named VRX-007 is very effective in suppressing the growth of tumors in experimental animals (Fig. 3). Importantly, VRX-007 is currently being evaluated in an FDA-approved clinical trial for cancer.
Fig. 2. Oncolytic adenovirus vectors kill cancer cells through the natural process of virus replication. The figure shows infection of a cancer cell with a single adenovirus particle (upper left), replication to produce progeny virus particles, and the lysis (disruption) of the cell and the release of progeny virus.
Fig. 3. The oncolytic adenovirus vector VRX-007 suppresses the growth of subcutaneous tumors in Syrian hamsters following intratumoral injection of the vector. The combination of VRX-007 with the chemotherapeutic drug cyclophosphamide (CP) is superior to either treatment alone.
In other research, we have developed the Syrian hamster as a unique animal model to study the pathogenesis of human adenoviruses and to evaluate the efficacy of drugs to treat adenovirus infections. Most tissues of the Syrian hamster are permissive for replication of adenovirus. Further, when the hamster is immunosuppressed by treatment with cyclophosphamide, replication continues for long periods (weeks) in the liver, lungs, and other organs. We have used this model to demonstrate that the drug named CMX001 (now named brincidofovir) inhibits Ad5 replication in immunosuppressed hamsters (Toth, K., et al., PNAS, 105, 7293-7297, 2008) (Fig. 4). We also have shown that cidofovir, ganciclovir, and valganciclovir are very effective against adenovirus infections in our immunosuppressed Syrian hamster model. Further studies are underway to evaluate the anti-adenovirus activity of a variety of other drugs.
CMX001 decreases adenovirus serotype 5 (Ad5) replication and Ad5-induced lesions in the liver. Livers of hamsters were sacrificed at day 6 after intravenous injection of Ad5 and then subjected to histopathological and immunohistochemistry (IHC) evaluation to detect Ad5 replication in the liver. Animals infected with Ad5 and not treated with CMX001 exhibited extensive coagulation necrosis throughout the liver (A) and widespread replication of Ad5, demonstrated by IHC staining for fiber (an Ad5 protein) (B). Treatment of Ad5-infected hamsters with CMX001 resulted in a significant reduction in hepatocellular injury (C) and greatly reduced IHC staining for fiber (D). The arrows indicate intranuclear inclusion bodies. (Scale bars: 200 _m for the larger images and 50 _m for Insets.) N, necrosis.
Dr. Wolds Lab
L to R: Ann Tollefson, Jackie Spencer, Bill Wold, Karoly Toth, Baoling Ying
Toth, K., Ying, B., Tollefson, A.E., Spencer, J.F., Balakrishnan, L., Sagartz, J.E., Buller, R.M.L., and Wold, W.S.M. (2015) Valganciclovir inhibits human adenovirus replication and toxicity in permissive immunosuppressed female and male Syrian hamsters. Viruses 7, 1409-1428.
Toth, K., Lee, S.R., Ying, B., Spencer, J.F., Tollefson, A.E., Sagartz, J.E., Kong, I-K., Wang, Z., and Wold, W.S.M. (2015) STAT2 knockout Syrian hamsters support enhanced replication and pathogenicity of human adenovirus, revealing an important role of Type I interferon response in viral control. PLOS Pathogens 8:e1005084.
Wold, W.S.M. and Toth, K. (2015) New drug on the horizon for treating adenoviruses. Expert Opinion in Pharmacology 16, 2095-2099.
Ying, B., Toth, K., Spencer, J.F., Aurora, R., and Wold, W.S.M. (2015) Transcriptome sequencing and development of an expression microarray platform for liver infection in adenovirus type-5 infected Syrian golden hamsters. Virology, 485, 305-312.
Dhar, D., Toth, K., and Wold, W.S.M. (2014) Cycles of transient high dose cyclophosphamide administration and intratumoral oncolytic adenovirus vector injection for long-term tumor suppression in Syrian hamsters. Cancer Gene Ther. 4, 1-8.
Ying, B., Tollefson, A.E., Spencer, J.A., Balakrishnan, L., Dewhurst, S., Capella, C., Buller, R.M.L., Toth, K., and Wold, W.S.M. (2014) Ganciclovir inhibits human adenovirus replication and toxicity in permissive immunosuppressed Syrian hamsters. Antimicrob. Agents and Chemotherapy 58, 7171-7181.
Tavis, J.E., Wang, H., Tollefson, A.E., Ying, B., Korom, M., Cheng, X., Cao, F., Davis, K.L., Wold, W.S.M., and Morrison, L.A. (2014) Inhibitors of nucleotidyl transferase superfamily enzymes suppress herpes simplex virus replication. Antimicrob. Agents and Chemotherapy 58, 7451-7461.
Tollefson, A.E., Spencer, J.F., Ying, B., Buller, R.M.L., Wold, W.S.M., and Toth, K. (2014) Cidofovir and brincidofovir reduce the pathology caused by systemic infection with human type 5 adenovirus in immunosuppressed Syrian hamsters, while ribavirin is largely ineffective in this model. Antiviral Res. 112, 38-46.
Spurrell, E., Gangeswaran, R., Wang, P., Cao, F., Gao, D., Feng, B., Wold, W.S.M., Tollefson, A., Lemoine, M.D., and Wang, Y.
STAT1 interaction with E3-14.7K in monocytesaffects the efficacy of oncolytic adenovirus.
J. Virol., 2014 88:2291-2230.
Wold, W.S.M., and Toth, K.
Adenovirus vectors for gene therapy, vaccination and cancer gene therapy.
Current Gene Therapy, 2013 13:421-433.
Murali, V., Ornelles, D., Gooding, L., Wilms, H., Huang, W., Tollefson, A., Wold, W.S.M., and Benson, C.
Adenovirus Death Protein (ADP) is required for lytic infection of human lymphocytes.
J. Virol., 2014 488:903-912.
Young, B.A., Spencer, J.F., Ying, B., Toth, K., and Wold, W.S.M.
The effects of radiation on antitumor efficacy of an oncolytic adenovirus vector in the Syrian hamster model.
Cancer Gene Therapy, 2013 20:531-537
Young, B.A., Spencer, J.F., Ying, B., Tollefson, A.E., Toth, K., and Wold, W.S.M.
The role of cyclophosphamide in enhancing antitumor efficacy of an adenovirus oncolytic vector in subcutaneous Syrian hamster tumors.
Cancer Gene Therapy, 2013 20:521-530
Wold, W.S.M. and Ison, M.G.
In Field’s Virology, 6thEdition (eds. D.M. Knipe and P.M. Howley)
Lippencott, Williams & Wilkins, Philadelphia, PA 2013 pp.1732-1767
Syrian hamster as a model for oncolytic adenovirus and to evaluate the efficacy of antiviral compounds.
Toth, K., and Wold, W.S.M.
Advances in Cancer Research 2012 115:69-92
Syrian hamster tumor model to study oncolytic Ad5 based vectors.
Dhar, D., Toth, K., and Wold, W.S.M.
In Oncolytic Viruses: Methods and Protocols, Humana Press, Inc., 2012 (eds. D.H. Kirn, T. Liu, and S.H. Thorne), Totowa, New Jersey, pp. 53-63.
Identification of a previously unidentified promoter that drives expression of the UXP transcription unit in the human adenovirus type 5 genome.
Ying, B., Tollefson, A.E., and Wold, W.S.M.
J. Virol. 2010 84:11470-11478
Increasing the efficacy of oncolytic adenovirus vectors.
Toth, K. and Wold, W.S.M.
Viruses 2010 2:1844-1866.
A fully replication-competent adenovirus vector with enhanced oncolytic properties.
Toth, K., Kuppuswamy, M., Shashkova, E.V., Spencer, J.F., and Wold, W.S.M.
Cancer Gene Ther. 2010 17, 761-770.
Oncolytic (replication-competent) adenoviruses as anticancer agents.
Toth K, Dhar D, Wold WS.
Expert Opin Biol Ther. 2010 Mar;10(3):353-68.PMID: 20132057 [PubMed - in process]Related articles
Adenovirus E1A and E1B-19K proteins protect human hepatoma cells from transforming growth factor beta1-induced apoptosis.
Tarakanova VL, Wold WS.
Virus Res. 2010 Jan;147(1):67-76. Epub 2009 Oct 23.PMID: 19854227 [PubMed - indexed for MEDLINE]Related articles
Pre-existing immunity and passive immunity to adenovirus 5 prevents toxicity caused by an oncolytic adenovirus vector in the Syrian hamster model.
Dhar D, Spencer JF, Toth K, Wold WS.
Mol Ther. 2009 Oct;17(10):1724-32. Epub 2009 Jul 14.PMID: 19602998 [PubMed - indexed for MEDLINE]Related articles
New pancreatic carcinoma model for studying oncolytic adenoviruses in the permissive Syrian hamster.
Spencer JF, Sagartz JE, Wold WS, Toth K.
Cancer Gene Ther. 2009 Dec;16(12):912-22. Epub 2009 May 29.PMID: 19478829 [PubMed - in process]Related articles
An acute toxicology study with INGN 007, an oncolytic adenovirus vector, in mice and permissive Syrian hamsters; comparisons with wild-type Ad5 and a replication-defective adenovirus vector.
Lichtenstein DL, Spencer JF, Doronin K, Patra D, Meyer JM, Shashkova EV, Kuppuswamy M, Dhar D, Thomas MA, Tollefson AE, Zumstein LA, Wold WS, Toth K.
Cancer Gene Ther. 2009 Aug;16(8):644-54. Epub 2009 Feb 6.PMID: 19197324 [PubMed - indexed for MEDLINE]Related articles
INGN 007, an oncolytic adenovirus vector, replicates in Syrian hamsters but not mice: comparison of biodistribution studies.
Ying B, Toth K, Spencer JF, Meyer J, Tollefson AE, Patra D, Dhar D, Shashkova EV, Kuppuswamy M, Doronin K, Thomas MA, Zumstein LA, Wold WS, Lichtenstein DL.
Cancer Gene Ther. 2009 Aug;16(8):625-37. Epub 2009 Feb 6.PMID: 19197322 [PubMed - indexed for MEDLINE]Related articles
Effect of preexisting immunity on oncolytic adenovirus vector INGN 007 antitumor efficacy in immunocompetent and immunosuppressed Syrian hamsters.
Dhar D, Spencer JF, Toth K, Wold WS.
J Virol. 2009 Mar;83(5):2130-9. Epub 2008 Dec 10.PMID: 19073718 [PubMed - indexed for MEDLINE]Related articlesFree article
Neuroadapted yellow fever virus strain 17D: a charged locus in domain III of the E protein governs heparin binding activity and neuroinvasiveness in the SCID mouse model.
Nickells J, Cannella M, Droll DA, Liang Y, Wold WS, Chambers TJ.
J Virol. 2008 Dec;82(24):12510-9. Epub 2008 Oct 8.PMID: 18842715 [PubMed - indexed for MEDLINE]Related articlesFree article
Immunosuppression enhances oncolytic adenovirus replication and antitumor efficacy in the Syrian hamster model.
Thomas MA, Spencer JF, Toth K, Sagartz JE, Phillips NJ, Wold WS.
Mol Ther. 2008 Oct;16(10):1665-73. Epub 2008 Jul 29.PMID: 18665155 [PubMed - indexed for MEDLINE]Related articles
Hexadecyloxypropyl-cidofovir, CMX001, prevents adenovirus-induced mortality in a permissive, immunosuppressed animal model.
Toth K, Spencer JF, Dhar D, Sagartz JE, Buller RM, Painter GR, Wold WS.
Proc Natl Acad Sci U S A. 2008 May 20;105(20):7293-7. Epub 2008 May 19.PMID: 18490659 [PubMed - indexed for MEDLINE]Related articlesFree article
West Nile 25A virus infection of B-cell-deficient ((micro)MT) mice: characterization of neuroinvasiveness and pseudoreversion of the viral envelope protein.
Chambers TJ, Droll DA, Walton AH, Schwartz J, Wold WS, Nickells J.
J Gen Virol. 2008 Mar;89(Pt 3):627-35.PMID: 18272752 [PubMed - indexed for MEDLINE]Related articlesFree article
Anticancer activity of oncolytic adenovirus vector armed with IFN-alpha and ADP is enhanced by pharmacologically controlled expression of TRAIL.
Shashkova EV, Kuppuswamy MN, Wold WS, Doronin K.
Cancer Gene Ther. 2008 Feb;15(2):61-72. Epub 2007 Nov 9.PMID: 17992200 [PubMed - indexed for MEDLINE]Related articles
Shashkova, E.V., Spencer, J.F., Wold, W.S.M., and Doronin, K. (2007) Targeting interferon-alpha pathway increases antitumor efficacy and reduces hepatotoxicity of E1A-mutated spread-enhanced oncolytic adenovirus. Molec. Ther. 15, 598-607.
Tollefson, A.E., Ying, B., Doronin, K., Sidor, P., and Wold, W.S.M. (2007) Identification of a new human adenovirus protein encoded by a novel late l-strand transcription unit. J. Virol. 81, 12918-12926. (Spotlighted as an article of significant interest).
Thomas, M.A., Spencer, J.F., La Regina, M.C., Dhar, D., Tollefson, A.E., Toth, K., and Wold, W.S.M.. (2006) Syrian hamster as a permissive immunocompetent animal model for the study of oncolytic adenovirus vectors. Cancer Res. 661270-1276. (Spotlighted as a Priority Report).