Herpesviruses as friends and enemies -
Herpes simplex virus vectors in gene therapy and novel antiviral treatment models
PI: Veijo Hukkanen, MDPhD, prof. m.a. Department of Virology, University of Turku
PhD Piritta Peri, MSc Michaela Nygårdas, MSc Riikka K. Mattila, MSc Henrik Paavilainen
E-mail veijo.hukkanen(at)utu.fi; tel. +358-2-333 7417
Herpes simplex virus (HSV) is a ubiquitous human pathogen, causing the recurrent labial herpes and genital herpes but, also more severe infections, such as herpes keratitis, neonatal herpes and the herpes encephalitis in rare cases.
The hallmark of HSV is the latent infection in sensory ganglia in the nervous system. Due to latency the resident HSV can not be totally eliminated by the antiviral chemotherapy, even though the acute clinical episodes can be successfully treated. However, there is a need to improve the antiviral therapy of herpes keratitis. Latency and the concomitant reactivation of HSV are key factors contributing to the pathogenesis of herpes encephalitis and neonatal herpes.
We study latency and its prevention, as well as means of therapeutic intervention of the acute HSV infection in the corneal epithelium and in cells of the nervous system.
We utilize organotypic ganglion cultures and long-term cultures of neuronal cells in the study.
We also study the cellular (innate) responses in HSV infections and aim at the control of HSV infection by RNA interference.
HSV is a promising backbone for gene therapy vector development, due to its neurotropism, immune evasion properties and the large genome with many dispensable genes. We develop novel HSV vectors utilizing the bacterial artificial chromosome (BAC) technology and study the gene therapy of nervous system diseases using HSV. Our disease model is murine EAE, serving as a model for multiple sclerosis (MS).
We develop new HSV vectors expressing favorable cytokines or neurotrophic factors. We also use RNA elements as therapeutic transgenes or for targeting the HSV vector. We develop means of delivery, targeting, and imaging of the HSV vectors. HSV with marker transgenes are utilized in the research of latency and pathogenesis. We study also the cellular responses and innate immunity to HSV and HSV vectors.
We develop diagnostic molecular methods for detection and study of HSV sequences in clinical specimens, thereby improving the virological diagnostics of severe HSV infections. We collaborate with research groups in Europe and in the USA (below). The project is funded by the Academy of Finland. Several PhD/MScD studies have been completed in our team.
Selected publications:
Nygårdas M., Aspelin C., Paavilainen H, Röyttä M, Waris M, Hukkanen V. Treatment of experimental autoimmune encephalomyelitis in SJL/J mice with a replicative HSV-1 vector expressing interleukin 5. Gene Therapy 18: 646-655, 2011
Peri P, Nuutila K, Vuorinen T, Saukko P, Hukkanen V: Cathepsins are involved in virus-induced cell death in ICP4 and Us3 deletion mutant herpes simplex virus type 1-infected monocytic cells, Journal of General Virology 92: 173-180, 2011.
Hukkanen V, Paavilainen H, Mattila RK: Host responses to herpes simplex virus (HSV) and HSV vectors, Future Virology, 5(4): 493-512, 2010.
Nygårdas M, Vuorinen T, Aalto A, Bamford D, Hukkanen V: Inhibition of Coxsackievirus B3 and related enteroviruses by antiviral short interfering RNA pools produced using phi6 RNA-dependent RNA polymerase, Journal of General Virology, 90:2468-2473, 2009.
Peri P, Mattila RK, Kantola H, Broberg EK, Waris M, Vuorinen T, Hukkanen V: Herpes Simplex Virus Type 1 Us3 Gene Deletion Influences Toll-like Receptor Responses in Cultured Monocytic Cells, Virology Journal, 5:140, 2008.
Broberg E, Peltoniemi J, Nygårdas M, Vahlberg T, Röyttä M, Hukkanen V. Spread and replication of and immune response to g134.5 negative herpes simplex virus type 1 vectors in BALB/c mice. Journal of Virology 78, 13139-13152, 2004.
Broberg, E., Setälä, N., Röyttä, M., Salmi, A., Erälinna, J-P., He, B., Roizman, B. & Hukkanen, V. Expression of interleukin-4 but not of interleukin-10 from a replicative herpes simplex virus type 1 viral vector precludes experimental allergic encephalomyelitis. Gene Therapy 8, 769-777, 2001.
Collaborations:
Prof. Bernard Roizman, University of Chicago
Prof. Beate Sodeik, University of Hannover Medical School
Prof. Ian Mohr, New York University School of Medicine
Prof. Ulrich Kalinke, Institute for Experimental Infection Research TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover
Prof. Dennis Bamford, University of Helsinki
Doc. Anthony Heape, University of Oulu
Doc. Sampsa Matikainen, Finnish Institute of Occupational Health
Prof. Stina Syrjänen, University of TurkuThe PET Center, University of Turku
Doc. Merja Soilu-Hänninen, Turku University Hospital
Doc. Laura Airas, Turku University Hospital
Doc. Matias Röyttä, Doc. Matti Waris, Doc. Tytti Vuorinen, University of Turku