Herpesviruses as friends and enemies

PI: Veijo Hukkanen, MDPhD, Department of Virology, University of Turku
PhD Outi Heikkilä, MSc Henrik Paavilainen, MSc Jenni Lehtinen, MD Jussi Palomäki, BSc Elina Ryödi, PhD Riikka K. Mattila (Universities of Oulu and Turku)
E-mail veijo.hukkanen (at); tel. +358-2-333 7417

Herpes simplex virus (HSV) is a common pathogen of humans, causing a spectrum of infections ranging from cold sores and genital herpes to the serious neonatal herpes infections and encephalitis. A characteristic feature of HSV is the latent infection in the nervous system, usually in sensory ganglia. The latent HSV infection is permanent, although recurrencies can be treated with antiviral drugs. Viral latency and reactivation are often the underlying etiologic factors in serious herpes infections.

We study latency of HSV and its prevention. We have at our disposal neuronal cell cultures and 3D-ganglion culture models of HSV infection. We elucidate the  innate immunity to HSV, and develop means for prevention and treatment of infection. We have a new RNA interference approach using enzymatically produced antiviral siRNA swarms for control of HSV infection.

HSV is a promising backbone for gene therapy vectors, due to its neurotropism, its immune evasion abilities, drug sensitivity and numerous other beneficial properties. An oncolytic HSV has just gained approval by the FDA and has received a positive opinion by the CHMP of the European Medicines Agency.  Our team has long-term experience in developing HSV vectors. We use now the bacterial artificial chromosome (BAC) technology and study the use of these attenuated viruses in gene therapy of central nervous system diseases. Our main disease model is the EAE (experimental autoimmune encephalomyelitis ) -  the disease model of human MS. Our research has produced new HSV vectors, from which therapeutic cytokines and trophic factors are expressed. We develop also oncolytic HSV for treatment of cancer. We improve delivery and targeting methods for HSV gene therapy. We study natural defenses and immune responses to HSV vectors and their backbones.

We elucidate genetic diversity among HSV strains from natural clinical isolates. We apply NGS sequencing methods suitable for analysis of large DNA viruses, in collaboration with a pioneer laboratory of the field. This research benefits both pathogenesis studies and virus vector development. We also improve molecular diagnostic methods for the herpes viruses in clinical diseases, having many decades of experience in HSV nucleic acid detection. We collaborate with significant domestic and international research groups (below). Our project has yielded many doctoral dissertations, in addition to numerous MSc theses and special projects in fields of biomedicine and other biosciences.

Selected Publications:

Paavilainen H, Romanovskaya A, Nygårdas M, Bamford D, Poranen M, Hukkanen V. Innate responses to small interfering RNA pools inhibiting herpes simplex virus infection in astrocytoid and epithelial cells. Innate Immunity, 21(4), 349-357, 2015.

Mattila RK, Harila K, Kangas SM, Paavilainen H, Heape AM, Mohr IJ, Hukkanen V: An investigation of herpes simplex virus type 1 latency in a novel mouse dorsal root ganglion model suggests a role for ICP34.5 in reactivation, Journal of General Virology, 96:2304-2313, 2015.

Mäki J, Paavilainen H, Grenman S, Syrjänen S, Hukkanen V. Carriage of herpes simplex virus and human papillomavirus in oral mucosa is rare in young women: A long-term prospective follow-up. Journal of Clinical Virology 70: 58-62, 2015.

Karttunen H., Savas J.N., McKinney C., Chen Y.-H., Yates J.R. 3rd, Hukkanen V., Huang T.T., Mohr I. Co-opting the Fanconi Anemia Genomic Stability Pathway Enables Herpesvirus DNA Synthesis and Productive Growth, Molecular Cell 55:111-122, 2014.

Nygårdas M, Paavilainen H, Müther N, Nagel C-H, Röyttä M, Sodeik B, Hukkanen V. A herpes simplex virus-derived replicative vector expressing LIF limits experimental demyelinating disease and modulates autoimmunity, PLoS One 8(5): e64200, 2013.

Romanovskaya A, Paavilainen H, Nygårdas M, Bamford H, Hukkanen V, Poranen M: Enzymatically produced pools of canonical and Dicer-substrate siRNA molecules display comparable gene silencing and antiviral activities against herpes simplex virus, PLoSOne 7(11): e51019, 2012.

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 Therapy18: 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.

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.

Hemling N, Röyttä M, Rinne J, Pöllänen P, Broberg E, Tapio V, Vahlberg T, Hukkanen V: Herpesviruses in brains in Alzheimer’s and Parkinson’s diseases, Annals of Neurology  54, 267-271, 2003.

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.

Main collaborations:
Dos. Laura Airas, University of Turku and Turku University Hospital
Dos. Petri Auvinen, University of Helsinki
Prof. Dennis Bamford and dos. Minna Poranen, University of Helsinki
Dos. Anthony Heape, University of Oulu
Prof. Ilkka Julkunen, University of Turku and National Institute for Health and Welfare
Prof. Igor Jurak, University of Rijeka, Croatia
Dos. Denis Kainov, Institute for Molecular Medicine Finland
Dos. Sampsa Matikainen, Finnish Institute of Occupational Health
Prof. Ian Mohr, New York University School of Medicine
Prof. Bernard Roizman, University of Chicago
Dos. Matias Röyttä, Turku University Hospital
Prof. Maria Teresa Sciortino, University of Messina
Prof. Beate Sodeik, University of Hannover Medical School
Prof. Stina Syrjänen, Institute of Dentistry, University of Turku Moriah L. Szpara, Pennsylvania State University
Dos. Maija Vihinen-Ranta, University of Jyväskylä