Microarray methods have the potential to replace some of the assays used in diagnostics. For example, the multiplex-PCR and microarray method () developed for detection of eight human herpesviruses can be further modified to be used in daily diagnostics of CNS infections. Sequential PCRs can be replaced with one microarray test. The microarray method is a qualitative assay, at least for now. However, microarrays can be used as screening tools in other than CNS infections, e.g. for CMV and EBV DNA detection from transplant patient samples, after which quantitative PCRs could be carried out on the microarray-positive samples. Therefore, fewer quantitative PCRs can be carried out, and in potential multi-infections, quantification can be performed for all the microarray-screened viruses with quantitative PCR. Serological microarrays could be used as a fast screening tool. In the future, when microarray technology has evolved and been tested more, perhaps serological assays such as EIAs could be replaced by microarrays. Developing of spotting equipments and reagents is proceeding, and reproducibility can be achieved faster.
In conclusion, microarray-based methods have showed the potential to be an efficient diagnostic assay. In the future, it is likely that the technique will be further developed to meet the requirements of routine diagnosis of viral infections.
ACKNOWLEDGEMENTS
Work for my thesis was carried out in the Department of Virology, Haartman Institute, University of Helsinki (HY) and Department of Virology, HUSLAB, Helsinki University Hospital. I would like to thank the Heads of the Departments of Virology, HY and HUSLAB, Professor Kalle Saksela and Docent Maija Lappalainen, respectively, for excellent discussions and providing a creative and enthusiastic environment. The Heads of Virology and Bacteriology, Department of General Microbiology, University of Helsinki, Professors Dennis Bamford and Timo Korhonen, are thanked for providing a pleasant atmosphere for post graduate studies and productive discussions.
I want to express my genuine gratitude to my supervisors, Professor Antti Vaheri and Docent
Heli Piiparinen. You are the dynamic duo that trusted me and helped me to make one of my
dreams come true. I warmly thank you, Antti, for guidance through these years and for your excellence in science. I will always remember You and your advices. Heli, you are a one of the most rational and intelligent person that I have ever met in my life. I deeply thank you for your guidance, and long and fruitful discussions in field of science, as well as in a “real” life. You challenged me and taught a lot.
I thank Docent Outi Monni and Professor Veijo Hukkanen for reviewing this thesis and for the constructive comments to improve my thesis. Veijo, thanks for the tips to our manuscript!
I would like to thank my co-authors and collaborators (in alphabetical order) Professor Anne Pitkäranta, Msc Kirsi Moilanen, Docent Maija Lappalainen, Docent Marjaleena Koskiniemi, PhD&MD Mervi Kanerva, BcS Minna Suvela, Professor Olli Vapalahti, and Docent Suvi Bühler. Especially, I want to thank Docent Maija Lappalainen for providing help and facilities for completing the thesis, and for supporting and believing in me whenever I had doubts! I want to thank Laura Mannonen (HUSLAB) for organizing samples and reference tests, and Auli Saarinen (formerly in Zoonosis Group), Kaija Sopenlehto (HUSLAB), Leena Kostamovaara (Zoonosis Group), and group of Neuro/Täsmä (HUSLAB) for their excellent and precise technical assistance.
I warmly thank my dear colleagues and friends Anu Jääskeläinen, Eili Huhtamo, Kirsi Moilanen, Niina Kivi, Niina Putkuri, Pia Jokela, Satu Kurkela and Tarja Sironen for the great company in a field of science, for instance, long “scientific sessions” in Hadanka (Helsinki), and for free time activities. There have been many occasions when we have (literally) rock the world!
I would also like to thank all the former and present members of Viral Zoonosis and Nemoses Group. Especially, I thank Agne, Alex, Angelina, Anna E., Anna Ka., Anna Kn., Erika, Hanni, Hao, Hilkka, Juha, Jussi, Kati, Kikka, Kirsi J., Liina, Maria, Oskari, Paula, Perttu, Pirjo, Suvi, Tomas, and Tytti. Other colleaques and friends in Haartman Institute, especially, Annu T., Camilla, Hannamari, Maaria, Vilja, Olya and Åse, are thanked for the companionship.
I would like to thank my new colleagues and co-workers in Mobidiag Ltd. I completed the thesis!
I thank my dear friends who balance my world and who have been there for me whenever I needed. Annu A., Asta, Elina V., Essi, Janne, Kalle V., Mikko J., Mikko V., Santtu, and Sara, without you the world would be too silent and still.
I deeply thank my husband Kalle J. for his love. You stand by me. For better and worse.
I You. My beloved daughter Ronja, you are the gold standard of my entire life. I thank my mother and father, Raija and Esko, and my sister Päivi, and her family, for their everlasting love and support.
Helsinki University Hospital, Laboratory Services (HUSLAB), Biomedicum Helsinki Foundation, Orion Foundation, Instrumentarium Foundation, Finnish National Technology Agency (Tekes), Paulo Foundation, Reseach Foundation of the University of Helsinki and Finnish Society for Study of Infectious Diseases (ITY ry) are thanked for financial support.
AJJ
Aalto, S.M., Juvonen, E., Tarkkanen, J., Volin, L., Ruutu, T., Mattila, P.S., Piiparinen, H., Knuutila, S. & Hedman, K. 2003, "Lymphoproliferative disease after allogeneic stem cell transplantation--pre-emptive diagnosis by quantification of Epstein-Barr virus DNA in serum", Journal of Clinical Virology, vol. 28, no. 3, pp. 275-283.
Aarnisalo, J., Ilonen, J., Vainionpää, R., Volanen, I., Kaitosaari, T. & Simell, O. 2003, "Development of antibodies against cytomegalovirus, varicella-zoster virus and herpes simplex virus in Finland during the first eight years of life: a prospective study", Scandinavian Journal of Infectious Diseases, vol. 35, no. 10, pp. 750-753.
Aberle, S.W. & Puchhammer-Stöckl, E. 2002, "Diagnosis of herpesvirus infections of the central nervous system", Journal of Clinical Virology, vol. 25 Suppl 1, pp. S79-85.
Alanen, A., Kahala, K., Vahlberg, T., Koskela, P. & Vainionpää, R. 2005, "Seroprevalence, incidence of prenatal infections and reliability of maternal history of varicella zoster virus, cytomegalovirus, herpes simplex virus and parvovirus B19 infection in South-Western Finland", BJOG, vol. 112, no. 1, pp. 50-56.
Albrecht, V., Chevallier, A., Magnone, V., Barbry, P., Vandenbos, F., Bongain, A., Lefebvre, J.C. & Giordanengo, V. 2006, "Easy and fast detection and genotyping of high-risk human papillomavirus by dedicated DNA microarrays", Journal of Virological Methods, vol. 137, no. 2, pp. 236-244.
Amon, W. & Farrell, P.J. 2005, "Reactivation of Epstein-Barr virus from latency", Reviews in Medical Virology, vol. 15, no. 3, pp. 149-156.
Arvin, A.M. 2001, "Varicella-Zoster Virus" in Fields Virology, eds. Knipe, D.M. & Howley, P.M., 4th edn, Lippincott Williams & Wilkins.
Ashley, R.L. 2002, "Performance and use of HSV type-specific serology test kits", Herpes, vol. 9, no. 2, pp. 38-45.
Ashley, R.L., Wu, L., Pickering, J.W., Tu, M.C. & Schnorenberg, L. 1998, "Premarket evaluation of a commercial glycoprotein G-based enzyme immunoassay for herpes simplex virus type- specific antibodies", Journal Clinical Microbiology, vol. 36, no. 1, pp. 294-295.
Ashley-Morrow, R., Krantz, E. & Wald, A. 2003, "Time course of seroconversion by HerpeSelect ELISA after acquisition of genital herpes simplex virus type 1 (HSV-1) or HSV-2", Sexually Transmitted Diseases, vol. 30, no. 4, pp. 310-314.
Baek, T.J., Park, P.Y., Han, K.N., Kwon, H.T. & Seong, G.H. 2008, "Development of a photodiode array biochip using a bipolar semiconductor and its application to detection of human papilloma virus", Anal.Bioanal Chem., Epub ahead of print.
Bergallo, M., Costa, C., Margio, S., Sidoti, F., Terlizzi, M.E. & Cavallo, R. 2007, "Development of a multiplex polymerase chain reaction for detection and typing of major human herpesviruses in cerebrospinal fluid", Canadian Journal of Microbiology, vol. 53, no. 10, pp. 1117-1122. Blank, H. & Brody, M.W. 1950, "Recurrent herpes simplex; a psychiatric and laboratory study",
Psychosomatic medicine, vol. 12, no. 4, pp. 254-260.
Blixt, O., Hoffmann, J., Svenson, S. & Norberg, T. 2007, "Pathogen specific carbohydrate antigen microarrays: a chip for detection of Salmonella O-antigen specific antibodies", Glycoconjugate Journal, vol. 25, no. 1, pp. 27-36.
Bonhomme, C.J., Nappez, C. & Raoult, D. 2007, "Microarray for serotyping of Bartonella species", BMC Microbiology, vol. 7, pp. 59.
Boriskin, Y.S., Rice, P.S., Stabler, R.A., Hinds, J., Al-Ghusein, H., Vass, K. & Butcher, P.D. 2004, "DNA microarrays for virus detection in cases of central nervous system infection", Journal of Clinical Microbiology, vol. 42, no. 12, pp. 5811-5818.
Borsting, C., Sanchez, J.J. & Morling, N. 2004, "Multiplex PCR, amplicon size and hybridization efficiency on the NanoChip electronic microarray", International Journal of Legal Medicine, vol. 118, no. 2, pp. 75-82.
Büchen-Osmond, C. 2007, Last update performed on 08-12-2007, The Universal Database of the International Committee on Taxonomy of Viruses [Access Date 02-03-2008] .
Calvario, A., Bozzi, A., Scarasciulli, M., Ventola, C., Seccia, R., Stomati, D. & Brancasi, B. 2002, "Herpes Consensus PCR test: a useful diagnostic approach to the screening of viral diseases of the central nervous system", Journal of Clinical Virology, vol. 25 Suppl 1, pp. S71-8. Cariani, E., Pollara, C.P., Valloncini, B., Perandin, F., Bonfanti, C. & Manca, N. 2007,
"Relationship between pp65 antigenemia levels and real-time quantitative DNA PCR for Human Cytomegalovirus (HCMV) management in immunocompromised patients", BMC Infectious Diseases, vol. 7, no. 1, pp. 138.
complex human cytomegalovirus genome: profiling kinetic class with drug sensitivity of viral gene expression", Journal of Virology, vol. 73, no. 7, pp. 5757-5766.
Chiu, S.S., Cheung, C.Y., Tse, C.Y. & Peiris, M. 1998, "Early diagnosis of primary human herpesvirus 6 infection in childhood: serology, polymerase chain reaction, and virus load", The Journal of Infectious Diseases, vol. 178, no. 5, pp. 1250-1256.
Chizhikov, V., Wagner, M., Ivshina, A., Hoshino, Y., Kapikian, A.Z. & Chumakov, K. 2002, "Detection and genotyping of human group A rotaviruses by oligonucleotide microarray hybridization", Journal of Clinical Microbiology, vol. 40, no. 7, pp. 2398-2407.
Chou, C.C., Lee, T.T., Chen, C.H., Hsiao, H.Y., Lin, Y.L., Ho, M.S., Yang, P.C. & Peck, K. 2006, "Design of microarray probes for virus identification and detection of emerging viruses at the genus level", BMC Bioinformatics, vol. 7, pp. 232.
Christophers, J., Clayton, J., Craske, J., Ward, R., Collins, P., Trowbridge, M. & Darby, G. 1998, "Survey of resistance of herpes simplex virus to acyclovir in northwest England", Antimicrobial Agents and Chemotherapy, vol. 42, no. 4, pp. 868-872.
Cohen, J.I. & Straus, S.E. 2001, "Varicella-zoster Virus and Its Replication" in Fields Virology, eds. Knipe, D.M. & Howley, P.M., 4th edn, Lippincott Williams & Wilkins.
Coiras, M.T., Lopez-Huertas, M.R., Lopez-Campos, G., Aguilar, J.C. & Perez-Brena, P. 2005, "Oligonucleotide array for simultaneous detection of respiratory viruses using a reverse-line blot hybridization assay", Journal of Medical Virology, vol. 76, no. 2, pp. 256-264.
Coriell, L.L. & Rake, G. 1950, "Electron microscopy of herpes simplex", Journal of Bacteriology, vol. 59, no. 1, pp. 61-8, illust.
Cretich, M., Damin, F., Pirri, G. & Chiari, M. 2006, "Protein and peptide arrays: recent trends and new directions", Biomolecular Engineering, vol. 23, no. 2-3, pp. 77-88.
Cunningham, A.L., Diefenbach, R.J., Miranda-Saksena, M., Bosnjak, L., Kim, M., Jones, C. & Douglas, M.W. 2006, "The cycle of human herpes simplex virus infection: virus transport and immune control", The Journal of Infectious Diseases, vol. 194 Suppl 1, pp. S11-8.
Dahlen, P.O., Iitia, A.J., Skagius, G., Frostell, A., Nunn, M.F. & Kwiatkowski, M. 1991, "Detection of human immunodeficiency virus type 1 by using the polymerase chain reaction and a time- resolved fluorescence-based hybridization assay", Journal of Clinical Microbiology, vol. 29, no. 4, pp. 798-804.
Daibata, M., Taguchi, T., Nemoto, Y., Taguchi, H. & Miyoshi, I. 1999, "Inheritance of chromosomally integrated human herpesvirus 6 DNA", Blood, vol. 94, no. 5, pp. 1545-1549. Davies, D.H., Wyatt, L.S., Newman, F.K., Earl, P.L., Chun, S., Hernandez, J.E., Molina, D.M.,
Hirst, S., Moss, B., Frey, S.E. & Felgner, P.L. 2008, "Antibody profiling by proteome microarray reveals the immunogenicity of the attenuated smallpox vaccine modified vaccinia virus ankara is comparable to that of Dryvax", Journal of Virology, vol. 82, no. 2, pp. 652-663. De Bolle, L., Van Loon, J., De Clercq, E. & Naesens, L. 2005, "Quantitative analysis of human
herpesvirus 6 cell tropism", Journal of Medical Virology, vol. 75, no. 1, pp. 76-85.
Diamond, C., Speck, C., Huang, M.L., Corey, L., Coombs, R.W. & Krieger, J.N. 2000, "Comparison of assays to detect cytomegalovirus shedding in the semen of HIV-infected men", Journal of Virological Methods, vol. 90, no. 2, pp. 185-191.
Druce, J., Catton, M., Chibo, D., Minerds, K., Tyssen, D., Kostecki, R., Maskill, B., Leong-Shaw, W., Gerrard, M. & Birch, C. 2002, "Utility of a multiplex PCR assay for detecting herpesvirus DNA in clinical samples", Journal of Clinical Microbiology, vol. 40, no. 5, pp. 1728-1732. Dworkin, R.H., Gnann, J.W.,Jr, Oaklander, A.L., Raja, S.N., Schmader, K.E. & Whitley, R.J. 2008,
"Diagnosis and assessment of pain associated with herpes zoster and postherpetic neuralgia", The Journal of Pain, vol. 9, no. 1 Suppl 1, pp. S37-44.
Echevarria, J.M., Casas, I., Tenorio, A., de Ory, F. & Martinez-Martin, P. 1994, "Detection of varicella-zoster virus-specific DNA sequences in cerebrospinal fluid from patients with acute aseptic meningitis and no cutaneous lesions", Journal of Medical Virology, vol. 43, no. 4, pp. 331-335.
Efstathiou, S. & Preston, C.M. 2005, "Towards an understanding of the molecular basis of herpes simplex virus latency", Virus Research, vol. 111, no. 2, pp. 108-119.
Epstein, M.A., Achong, B.G. & Barr, Y.M. 1964, "Virus Particles in Cultured Lymphoblasts from Burkitt's Lymphoma", Lancet, vol. 1, pp. 702-703.
Erlich, K.S. 1997, "Management of herpes simplex and varicella-zoster virus infections", The Western Journal of Medicine, vol. 166, no. 3, pp. 211-215.
Espy, M.J., Teo, R., Ross, T.K., Svien, K.A., Wold, A.D., Uhl, J.R. & Smith, T.F. 2000, "Diagnosis of varicella-zoster virus infections in the clinical laboratory by LightCycler PCR", Journal of
Forward, K.R. & Lee, S.H. 2003, "Predominance of herpes simplex virus type 1 from patients with genital herpes in Nova Scotia", The Canadian Journal of Infectious Diseases, vol. 14, no. 2, pp. 94-96.
Frenkel, N., Schirmer, E.C., Wyatt, L.S., Katsafanas, G., Roffman, E., Danovich, R.M. & June, C.H. 1990, "Isolation of a new herpesvirus from human CD4+ T cells", Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 2, pp. 748-752. Furuta, Y., Ohtani, F., Aizawa, H., Fukuda, S., Kawabata, H. & Bergstrom, T. 2005, "Varicella-
zoster virus reactivation is an important cause of acute peripheral facial paralysis in children", The Pediatric Infectious Disease Journal, vol. 24, no. 2, pp. 97-101.
Garner, J.A. 2003, "Herpes simplex virion entry into and intracellular transport within mammalian cells", Advanced Drug Delivery Reviews, vol. 55, no. 11, pp. 1497-1513.
Gemignani, F., Landi, S., Chabrier, A., Smet, A., Zehbe, I., Canzian, F. & Tommasino, M. 2004, "Generation of a DNA microarray for determination of E6 natural variants of human papillomavirus type 16", Journal of Virological Methods, vol. 119, no. 2, pp. 95-102.
Gheit, T., Landi, S., Gemignani, F., Snijders, P.J., Vaccarella, S., Franceschi, S., Canzian, F. & Tommasino, M. 2006, "Development of a sensitive and specific assay combining multiplex PCR and DNA microarray primer extension to detect high-risk mucosal human papillomavirus types", Journal of Clinical Microbiology, vol. 44, no. 6, pp. 2025-2031.
Gilden, D.H., Mahalingam, R., Cohrs, R.J. & Tyler, K.L. 2007, "Herpesvirus infections of the nervous system", Nature Clinical Practice Neurology, vol. 3, no. 2, pp. 82-94.
Gleaves, C.A., Smith, T.F., Shuster, E.A. & Pearson, G.R. 1984, "Rapid detection of cytomegalovirus in MRC-5 cells inoculated with urine specimens by using low-speed centrifugation and monoclonal antibody to an early antigen", Journal of Clinical Microbiology, vol. 19, no. 6, pp. 917-919.
Gopal, M.R., Thomson, B.J., Fox, J., Tedder, R.S. & Honess, R.W. 1990, "Detection by PCR of HHV-6 and EBV DNA in blood and oropharynx of healthy adults and HIV-seropositives", Lancet, vol. 335, no. 8705, pp. 1598-1599.
Guatelli, J.C., Gingeras, T.R. & Richman, D.D. 1989, "Nucleic acid amplification in vitro: detection of sequences with low copy numbers and application to diagnosis of human immunodeficiency virus type 1 infection", Clinical Microbiology Reviews, vol. 2, no. 2, pp. 217- 226.
Guo, Z., Guilfoyle, R.A., Thiel, A.J., Wang, R. & Smith, L.M. 1994, "Direct fluorescence analysis of genetic polymorphisms by hybridization with oligonucleotide arrays on glass supports", Nucleic Acids Research, vol. 22, no. 24, pp. 5456-5465.
Hambleton, S. & Gershon, A.A. 2005, "Preventing varicella-zoster disease", Clinical Microbiology Reviews, vol. 18, no. 1, pp. 70-80.
Hanson, K.E., Alexander, B.D., Woods, C., Petti, C. & Reller, L.B. 2007, "Validation of laboratory screening criteria for herpes simplex virus testing of cerebrospinal fluid", Journal of Clinical Microbiology, vol. 45, no. 3, pp. 721-724.
Harnden, D.G., Elsdale, T.R., Young, D.E. & Ross, A. 1967, "The isolation of cytomegalovirus from peripheral blood", Blood, vol. 30, no. 1, pp. 120-125.
He, M., Stoevesandt, O., Palmer, E.A., Khan, F., Ericsson, O. & Taussig, M.J. 2008, "Printing protein arrays from DNA arrays", Nature Methods, vol. 5, no. 2, pp. 175-177.
Hill, J.M., Sedarati, F., Javier, R.T., Wagner, E.K. & Stevens, J.G. 1990, "Herpes simplex virus latent phase transcription facilitates in vivo reactivation", Virology, vol. 174, no. 1, pp. 117- 125.
Ho, M. 2007, "The history of cytomegalovirus and its diseases", Medical Microbiology and Immunology, Dec. 18.
Hsia, C.C., Chizhikov, V.E., Yang, A.X., Selvapandiyan, A., Hewlett, I., Duncan, R., Puri, R.K., Nakhasi, H.L. & Kaplan, G.G. 2007, "Microarray multiplex assay for the simultaneous detection and discrimination of hepatitis B, hepatitis C, and human immunodeficiency type-1 viruses in human blood samples", Biochemical and Biophysical Research Communications, vol. 356, no. 4, pp. 1017-1023.
Huber, M., Mundlein, A., Dornstauder, E., Schneeberger, C., Tempfer, C.B., Mueller, M.W. & Schmidt, W.M. 2002, "Accessing single nucleotide polymorphisms in genomic DNA by direct multiplex polymerase chain reaction amplification on oligonucleotide microarrays", Analytical Biochemistry, vol. 303, no. 1, pp. 25-33.
Hudnall, S.D., Chen, T. & Tyring, S.K. 2004, "Species identification of all eight human herpesviruses with a single nested PCR assay", Journal of Virological Methods, vol. 116, no. 1,
Clinical Microbiology, vol. 38, no. 9, pp. 3214-3218.
Hukkanen, V. & Vuorinen, T. 2002, "Herpesviruses and enteroviruses in infections of the central nervous system: a study using time-resolved fluorometry PCR", Journal of Clinical Virology, vol. 25 Suppl 1, pp. S87-94.
Hukkanen V., Suni J., Lautenschlager I. & Linnavuori K. 2003, "Herpesvirusten ryhmä" in Mikrobiologia ja infektiosairaudet (Kirja I), eds. P. Huovinen, S. Meri, H. Peltola, M. Vaara, A. Vaheri & V. Valtonen, 1st edn, Gummerus Kirjapaino Oy, Jyväskylä, Finland.
Hummel, M. & Abecassis, M.M. 2002, "A model for reactivation of CMV from latency", Journal of Clinical Virology, vol. 25 Suppl 2, pp. S123-36.
Hurt, C. & Tammaro, D. 2007, "Diagnostic evaluation of mononucleosis-like illnesses", The American Journal of Medicine, vol. 120, no. 10, pp. 911.e1-911.e8.
Ihira, M., Yoshikawa, T., Ishii, J., Nomura, M., Hishida, H., Ohashi, M., Enomoto, Y., Suga, S., Iida, K., Saito, Y., Nishiyama, Y. & Asano, Y. 2002, "Serological examination of human herpesvirus 6 and 7 in patients with coronary artery disease", Journal of Medical Virology, vol. 67, no. 4, pp. 534-537.
Jackson, R., Morris, D.J., Cooper, R.J., Bailey, A.S., Klapper, P.E., Cleator, G.M. & Tullo, A.B. 1996, "Multiplex polymerase chain reaction for adenovirus and herpes simplex virus in eye swabs", Journal of Virological Methods, vol. 56, no. 1, pp. 41-48.
Jarvis, M.A. & Nelson, J.A. 2002, "Human cytomegalovirus persistence and latency in endothelial cells and macrophages", Current Opinion in Microbiology, vol. 5, no. 4, pp. 403-407.
Junker, A.K. 2005, "Epstein-Barr virus", Pediatrics in review / American Academy of Pediatrics, vol. 26, no. 3, pp. 79-85.
Jääskeläinen, A.J. & Maunula, L. 2006, "Applicability of microarray technique for the detection of noro- and astroviruses", Journal of Virological Methods, vol. 136, no. 1-2, pp. 210-216. Kallio-Kokko, H., Vapalahti, O., Lundkvist, A. & Vaheri, A. 1998, "Evaluation of Puumala virus
IgG and IgM enzyme immunoassays based on recombinant baculovirus-expressed nucleocapsid protein for early nephropathia epidemica diagnosis", Clinical and Diagnostic Virology, vol. 10, no. 1, pp. 83-90.
Kanerva, M., Mannonen, L., Piiparinen, H., Peltomaa, M., Vaheri, A. & Pitkäranta, A. 2007, "Search for Herpesviruses in cerebrospinal fluid of facial palsy patients by PCR", Acta Oto- Laryngologica, vol. 127, no. 7, pp. 775-779.
Kennedy, P.G. 2002, "Varicella-zoster virus latency in human ganglia", Reviews in Medical Virology, vol. 12, no. 5, pp. 327-334.
Kieff, E. 1995, "Epstein-Barr virus--increasing evidence of a link to carcinoma", The New England Journal of Medicine, vol. 333, no. 11, pp. 724-726.
Kieff, E. & Levine, J. 1974, "Homology between Burkitt herpes viral DNA and DNA in continuous lymphoblastoid cells from patients with infectious mononucleosis", Proceedings of the National Academy of Sciences of the United States of America, vol. 71, no. 2, pp. 355-358. Kimberlin, D.W. 2004, "Neonatal herpes simplex infection", Clinical Microbiology Reviews, vol. 17,
no. 1, pp. 1-13.
Kimura, H., Morita, M., Yabuta, Y., Kuzushima, K., Kato, K., Kojima, S., Matsuyama, T. & Morishima, T. 1999, "Quantitative analysis of Epstein-Barr virus load by using a real-time PCR assay", Journal of Clinical Microbiology, vol. 37, no. 1, pp. 132-136.
Klaassen, C.H., Prinsen, C.F., de Valk, H.A., Horrevorts, A.M., Jeunink, M.A. & Thunnissen, F.B. 2004, "DNA microarray format for detection and subtyping of human papillomavirus", Journal of Clinical Microbiology, vol. 42, no. 5, pp. 2152-2160.
Kneitz, R.H., Schubert, J., Tollmann, F., Zens, W., Hedman, K. & Weissbrich, B. 2004, "A new method for determination of varicella-zoster virus immunoglobulin G avidity in serum and cerebrospinal fluid", BMC Infectious Diseases, vol. 4, pp. 33.
Korimbocus, J., Scaramozzino, N., Lacroix, B., Crance, J.M., Garin, D. & Vernet, G. 2005, "DNA probe array for the simultaneous identification of herpesviruses, enteroviruses, and flaviviruses", Journal of Clinical Microbiology, vol. 43, no. 8, pp. 3779-3787.
Koskiniemi, M., Mannonen, L., Kallio, A. & Vaheri, A. 1997, "Luminometric microplate hybridization for detection of varicella-zoster virus PCR product from cerebrospinal fluid", Journal of Virological Methods, vol. 63, no. 1-2, pp. 71-79.
Koskiniemi, M., Rantalaiho, T., Piiparinen, H., von Bonsdorff, C.H., Färkkilä, M., Järvinen, A., Kinnunen, E., Koskiniemi, S., Mannonen, L., Muttilainen, M., Linnavuori, K., Porras, J., Puolakkainen, M., Raiha, K., Salonen, E.M., Ukkonen, P., Vaheri, A., Valtonen, V. & Study Group. 2001, "Infections of the central nervous system of suspected viral origin: a
zoster virus infections", Journal of Clinical Virology, vol. 25, no. 3, pp. 293-301.
Kovanen, J. 2007a, "Aivokalvotulehdukset" in Lääkärin käsikirja, ed. I. Kunnamo, Kustannus Oy Duodecim, Helsinki, Finland, Access Date 10-29-2007.
Kovanen, J. 2007b, "Enkefaliitit" in Lääkärin käsikirja, ed. I. Kunnamo, Kustannus Oy Duodecim, Helsinki, Finland, Access Date 10-29-2007.
Kupila, L., Vainionpää, R., Vuorinen, T., Marttila, R.J. & Kotilainen, P. 2004, "Recurrent lymphocytic meningitis: the role of herpesviruses", Archives of Neurology, vol. 61, no. 10, pp. 1553-1557.
Kupila, L., Vuorinen, T., Vainionpää, R., Hukkanen, V., Marttila, R.J. & Kotilainen, P. 2006, "Etiology of aseptic meningitis and encephalitis in an adult population", Neurology, vol. 66, no. 1, pp. 75-80.
Kwon, J.A., Lee, H., Lee, K.N., Chae, K., Lee, S., Lee, D.K. & Kim, S. 2008, "High diagnostic accuracy of antigen microarray for sensitive detection of hepatitis C virus infection", Clinical chemistry, vol. 54, no. 2, pp. 424-428.
La Rosa, C., Wang, Z., Lacey, S.F., Markel, S.F., Sharma, M.C., Martinez, J., Lalimarmo, M.M. & Diamond, D.J. 2005, "Characterization of host immunity to cytomegalovirus pp150 (UL32)",