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Sequence Variation of Human Jc and Bk Polyomaviruses in the Pathogenesis of Polyomavirus-Associated Diseases

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Sequence Variation of Human Jc and Bk Polyomaviruses in the Pathogenesis of Polyomavirus-Associated Diseases Hanna Liimatainen SEQUENCE VARIATION OF HUMAN JC AND BK POLYOMAVIRUSES IN THE PATHOGENESIS OF POLYOMAVIRUS-ASSOCIATED DISEASES POLYOMAVIRUS-ASSOCIATED OF THE PATHOGENESIS IN SEQUENCE VARIATION OF HUMAN JC AND BK POLYOMAVIRUSES AND BK JC HUMAN OF VARIATION SEQUENCE IN THE PATHOGENESIS OF POLYOMAVIRUS-ASSOCIATED DISEASES Hanna Liimatainen Faculty of Medicine University of Helsinki 2019 SEQUENCE VARIATION OF HUMAN JC AND BK POLYOMAVIRUSES IN THE PATHOGENESIS OF POLYOMAVIRUS-ASSOCIATED DISEASES HANNA LIIMATAINEN Department of Virology Medicum, Faculty of Medicine University of Helsinki and Department of Virology and Immunology Division of Clinical Microbiology Helsinki University Hospital Laboratory ACADEMIC DISSERTATION To be presented, with the permission of the Faculty of Medicine of the University of Helsinki, for public examination in Lecture Hall 1, Haartman Institute, on Friday 10th of January 2020, at 12 noon. Helsinki 2019 7ǗǜȨǚǖǣǙǝǚ Eeva Auvinen, PhD, Docent Department of Virology and Immunology Helsinki University Hospital Laboratory and Department of Virology Medicum, Faculty of Medicine University of Helsinki Helsinki, Finland 6ȨǖǣȨǕȨǚǙ Varpu Marjomäki, PhD, Docent Department of Biological and Environmental Science Nanoscience Center University of Jyväskylä Jyväskylä, Finland Matti Jalasvuori, PhD, Docent Department of Biological and Environmental Science Nanoscience Center University of Jyväskylä Jyväskylä, Finland 3ǜǜǝǞȨǞǘ Ugo Moens, PhD, Professor 1SPIGYPEV-RƽEQQEXMSR6IWIEVGL+VSYT 1-6+ Department of Medical Biology Faculty of Health Sciences University of Tromsø Tromsø, Norway Cover illustration by Niclas Liimatainen -7&2 TETIVFEGO -7&2 4(* Hansaprint Helsinki 2019 8LI*EGYPX]SJ1IHMGMRIYWIWXLI9VOYRHW]WXIQ TPEKMEVMWQVIGSKRMXMSR XSI\EQMRIEPP doctoral dissertations. To Niclas and Elias CONTENTS LIST OF ORIGINAL PUBLICATIONS..................................................................................... I ABBREVIATIONS.................................................................................................................. II ABSTRACT........................................................................................................................... III TIIVISTELMÄ (ABSTRACT IN FINNISH)............................................................................ IV INTRODUCTION................................................................................................................... V 1 LITERATURE REVIEW........................................................................................................ 1 -ǟǟǗǞȨǙǓǙǘȨǟƁȳǙǝǜǤǣǙǘǣȱȳǘȨȰȰȨǦȨǞǙȨǟȳȱǤǣǞȨǚǓ............................................ 1 1.1.1 Viral infections in immunosuppressed patients.............................................................. 1 ,ǗǟȳǞǜǝǠǓǝǟȳǖǣǚǗǙȨǙƁȳǥǚǝǗǜǝǦȨǟȨǚǥǣǞǥǤǗǟȳǞǜȳǘǤǝǥȨǞǙ........................ 2 1.2.1 Epidemiology of human polyomaviruses.......................................................................... 2 1.2.2 Molecular biology of human polyomaviruses.................................................................. 5 1.2.3 Polyomaviruses as human pathogens.............................................................................. 6 .'ȳǞȰ&/ǜǝǠǓǝǟȳǖǣǚǗǙȨǙƁǘǤȨǦǣǚǙǘǤǗǟȳǞǜǝǠǓǝǟȳǖǣǚǗǙȨǙǘǝȲȨȰǣǙȱǝǖȨǚȨȰ 8 1.3.1 Molecular biology................................................................................................................. 8 1.3.2 Viral life cycle........................................................................................................................ 13 4ǚǝǥǚȨǙǙǣǖȨǟǗǠǘǣǦǝȱȳǠǠȨǗǡǝȨǞȱȨǜǤȳǠǝǜȳǘǤǓ.................................................... 14 1.4.1 PML is due to infection of neurotropic JC polyomavirus............................................ 14 1.4.2 Sequence variation of JC polyomavirus......................................................................... 18 4ǝǠǓǝǟȳǖǣǚǗǙȳǙǙǝȱǣȳǘȨȰǞȨǜǤǚǝǜȳǘǤǓ................................................................ 21 1.5.1 BKPVAN results from uncontrolled replication of BK polyomavirus......................... 21 1.5.2 Sequence variation of BK polyomavirus......................................................................... 23 1.5.3 JC polyomavirus-associated nephropathy..................................................................... 25 1ȳǙǙǣǖȨǜȳǚȳǠǠȨǠǙȨǛǗȨǞȱǣǞǥ 1.6.1 Novel high-throughput sequencing techniques............................................................. 26 1.6.2 Library preparation, data analysis, and pitfalls in sequencing.................................... 29 1.6.3 Massive parallel sequencing in virological diagnostics............................................... 30 1.6.4 Ethical considerations........................................................................................................ 30 2 AIMS................................................................................................................................. 31 3 EXPERIMENTAL DESIGN................................................................................................ 32 7ȳǟǜǠȨǟȳǘȨǚǣȳǠȳǞȰȱǠǣǞǣȱȳǠȱǤȳǚȳȱǘȨǚǣǙǘǣȱǙǝǦǜȳǘǣȨǞǘǙ 3.1.1 PML patients (I).................................................................................................................... 32 3.1.2 Kidney transplant patients with JCPyV viruria (II)......................................................... 33 3.1.3 Kidney transplant patients with BKPyV viremia (III, IV)................................................ 34 3.1.4 Ethical permission............................................................................................................... 35 8ǝǘȳǠǞǗȱǠȨǣȱȳȱǣȰȨǔǘǚȳȱǘǣǝǞ --: 5ǗȳǞǘǣǘȳǘǣǖȨ8ȳǛǟȳǞǚȨȳǠǘǣǟȨ4'6 --: 'ǤȳǚȳȱǘȨǚǣǒȳǘǣǝǞǝǦȱǝǟǜǠȨǘȨ.'4Ǔ:ǥȨǞǝǟȨǙ --- %QTPMƼGEXMSRSJGSQTPIXIZMVEPKIRSQI 3.4.2 Single-molecule real-time sequencing and sequence analysis.................................. 37 3.4.3 Characterization of complete JCPyV sequences.......................................................... 37 'ǤȳǚȳȱǘȨǚǣǒȳǘǣǝǞǝǦǘǚȳǞǙȱǚǣǜǘǣǝǞȳǠȱǝǞǘǚǝǠǚȨǥǣǝǞǝǦ&/4Ǔ: ----: %QTPMƼGEXMSRSJ&/4]:8'6 8EVKIXIHWLSVXVIEHWIUYIRGMRK 3.5.3 Sequence analysis................................................................................................................ 38 &/4Ǔ:ǟǣȱǚǝ62%ȳǞȳǠǓǙǣǙ --- 4 RESULTS AND DISCUSSION........................................................................................... 40 'ǤȳǚȳȱǘȨǚǣǒȳǘǣǝǞ ǝǦ ȱǝǟǜǠȨǘȨ .' ǜǝǠǓǝǟȳǖǣǚǗǙ ǥȨǞǝǟȨǙ ȳǙǙǝȱǣȳǘȨȰ ǕǣǘǤ 410 ȳǞȰ.'4:%2 --- 4.1.1 Sequence data...................................................................................................................... 40 2''6 4.1.3 Genotypes............................................................................................................................. 45 4.1.4 Mutations within the VP1................................................................................................... 46 1YXEXMSRW[MXLMRXLI08EK &/4Ǔ:8'6ǚȨȳǚǚȳǞǥȨǟȨǞǘǙǣǞ&/4:%2 ----: 4.2.1 Sequence data...................................................................................................................... 50 8'6 )JJIGXSJ8'6VIEVVERKIQIRXWSRXVERWGVMTXMSRJEGXSVFMRHMRKWMXIW &/4Ǔ:ǟǣȱǚǝ62%ȨǔǜǚȨǙǙǣǝǞǣǞ&/4:%2 --- 8ǤȨǚǝǠȨǝǦǖǣǚȳǠǟǗǘȳǘǣǝǞǙǣǞ410ȳǞȰǜǝǠǓǝǟȳǖǣǚǗǙȳǙǙǝȱǣȳǘȨȰǞȨǜǤǚǝǜȳǘǤǓ 5 CONCLUDING REMARKS................................................................................................ 59 6 ACKNOWLEDGEMENTS.................................................................................................. 61 %44)2(-')7 6)*)6)2')7 9 ORIGINAL PUBLICATIONS.............................................................................................. 82 LIST OF ORIGINAL PUBLICATIONS This thesis is based on the following publications: I Seppälä H., Virtanen E., Saarela M., Laine P., Paulín L., Mannonen L., Auvinen P., Auvinen E. Single-molecule sequencing revealing the presence of distinct JC polyomavirus populations in patients with progressive multifocal leukoencephalopathy. .-RJIGX(MW Ɓ II 7ITTʞPʞ ,1 ,IPERXIVʞ -8 0EMRI 4/7 0EYXIRWGLPEKIV -8 4EYPʧR 0+ Jahnukainen TJ., Auvinen POV., Auvinen E. Archetype JC polyomavirus .'4]: TVIZEMPW MR E VEVI GEWI SJ .'4]: RITLVSTEXL] ERH MR WXEFPI VIREP XVERWTPERXVIGMTMIRXW[MXL.'4]:ZMVYVME.-RJIGX(MW III Virtanen E.*, Seppälä H.*, Helanterä I., Laine P., Lautenschlager I., Paulin L., Mannonen L., Auvinen P., Auvinen E. BK polyomavirus microRNA expression and sequence variation in polyomavirus-associated nephropathy. J Clin Virol IV 0MMQEXEMRIR , ;IWIWPMRHXRIV 0 7XVEWWP 6 %FIVPI 7; &SRH + %YZMRIR E. Next-generation sequencing shows marked rearrangements of BK polyomavirus that favor but are not required for polyomavirus-associated RITLVSTEXL] )TYFELIEHSJTVMRX *The authors have contributed equally to the study. Article III has also been used in the dissertation entitled Diagnostics and monitoring of chronic virus infections: evaluation of novel molecular methods and markers by :MVXERIR) *EGYPX]SJ1IHMGMRI9RMZIVWMX]SJ,IPWMROM The original publications are referred to in the text by their Roman numerals. The TETIVW-Ɓ-:EVIVITVMRXIH[MXLXLIOMRHTIVQMWWMSRSJ3\JSVH9RMZIVWMX]4VIWWERH Elsevier. I ABBREVIATIONS ALTO Alternate frame of the LTag reading frame BKPVAN BK polyomavirus-associated nephropathy BKPyV BK polyomavirus bp Base pair cART Combined antiretroviral therapy CTL Cytotoxic T lymphocyte HPyV10 Human polyomavirus 10 HPyV12 Human polyomavirus 12 ,4]: ,YQERTSP]SQEZMVYW HPyV7 Human polyomavirus 7 HPyV9 Human polyomavirus 9 JCPVAN JC polyomavirus-associated nephropathy JCPyV JC polyomavirus KIPyV Karolinska Institute
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