1887

Journal of General Virology header logo

Volume 93, Issue 8

BK polyomavirus with archetypal and rearranged non-coding control regions is present in cerebrospinal fluids from patients with neurological complications Free

Abstract

BK polyomavirus (BKPyV) has recently been postulated as an emerging opportunistic pathogen of the human central nervous system (CNS), but it is not known whether specific strains are associated with the neurotropic character of BKPyV. The presence of BKPyV large T-antigen DNA was examined in 2406 cerebrospinal fluid (CSF) samples from neurological patients with suspected JC polyomavirus infection. Twenty patients had a large T-antigen DNA-positive specimen. The non-coding control region (NCCR) of the BKPyV strains amplified from CSF from these 20 patients, strains circulating in renal and bone marrow transplant recipients and from healthy pregnant women was sequenced. The archetypal conformation was the most prevalent in all groups and 14 of the neurological patients harboured archetypal strains, while the remaining six patients possessed BKPyV with rearranged NCCR similar to previously reported variants from non-neurological patients. Transfection studies in Vero cells revealed that five of six early and four of six late rearranged promoters of these CSF isolates showed significantly higher activity than the corresponding archetypal promoter. From seven of the neurological patients with BKPyV DNA-positive CSF, paired serum samples were available. Five of them were negative for BKPyV DNA, while serum from the remaining two patients harboured BKPyV strains with archetypal NCCR that differed from those present in their CSF. Our results suggest that NCCR rearrangements are not a hallmark for BKPyV neurotropism and the dissemination of a rearranged NCCR from the blood may not be the origin of BKPyV CNS infection.

  • Received:
  • Accepted:
  • Published Online:
© 2012 SGM
Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.042143-0
2012-08-01
2024-04-16
Loading full text...

Full text loading...

/deliver/fulltext/jgv/93/8/1780.html?itemId=/content/journal/jgv/10.1099/vir.0.042143-0&mimeType=html&fmt=ahah

References

  1. Allander T., Andreasson K., Gupta S., Bjerkner A., Bogdanovic G., Persson M. A., Dalianis T., Ramqvist T., Andersson B. 2007; Identification of a third human polyomavirus. J Virol 81:4130–4136 [View Article][PubMed]
     [Google Scholar]
  2. Anzivino E., Bellizzi A., Mitterhofer A. P., Tinti F., Barile M., Colosimo M. T., Fioriti D., Mischitelli M., Chiarini F. other authors 2011; Early monitoring of the human polyomavirus BK replication and sequencing analysis in a cohort of adult kidney transplant patients treated with basiliximab. Virol J 8:407 [View Article][PubMed]
     [Google Scholar]
  3. Arthur R. R., Dagostin S., Shah K. V. 1989; Detection of BK virus and JC virus in urine and brain tissue by the polymerase chain reaction. J Clin Microbiol 27:1174–1179[PubMed]
     [Google Scholar]
  4. Bárcena-Panero A., Van Ghelue M., Khan M. T., Echevarría J. E., Fedele G., Moens U. 2012; BK virus-associated infection in cerebrospinal fluid of neurological patients and mutation analysis of the complete VP1 gene in different patient groups. J Cell Physiol 227:136–145 [View Article][PubMed]
     [Google Scholar]
  5. Behre G., Becker M., Christopeit M. 2008; BK virus encephalitis in an allogeneic hematopoietic stem cell recipient. Bone Marrow Transplant 42:499 [View Article][PubMed]
     [Google Scholar]
  6. Behzad-Behbahani A., Klapper P. E., Vallely P. J., Cleator G. M. 2003a; BK virus DNA in CSF of immunocompetent and immunocompromised patients. Arch Dis Child 88:174–175 [View Article][PubMed]
     [Google Scholar]
  7. Behzad-Behbahani A., Klapper P. E., Vallely P. J., Cleator G. M., Bonington A. 2003b; BKV-DNA and JCV-DNA in CSF of patients with suspected meningitis or encephalitis. Infection 31:374–378[PubMed]
     [Google Scholar]
  8. Bendiksen S., Rekvig O. P., Van Ghelue M., Moens U. 2000; VP1 DNA sequences of JC and BK viruses detected in urine of systemic lupus erythematosus patients reveal no differences from strains expressed in normal individuals. J Gen Virol 81:2625–2633[PubMed]
     [Google Scholar]
  9. Bhattacharjee S., Chakraborty T. 2004; High reactivation of BK virus variants in Asian Indians with renal disorders and during pregnancy. Virus Genes 28:157–168 [View Article][PubMed]
     [Google Scholar]
  10. Bofill-Mas S., Pina S., Girones R. 2000; Documenting the epidemiologic patterns of polyomaviruses in human populations by studying their presence in urban sewage. Appl Environ Microbiol 66:238–245 [View Article][PubMed]
     [Google Scholar]
  11. Boldorini R., Veggiani C., Turello E., Barco D., Monga G. 2005; Are sequence variations in the BK virus control region essential for the development of polyomavirus nephropathy?. Am J Clin Pathol 124:303–312 [View Article][PubMed]
     [Google Scholar]
  12. Boldorini R., Allegrini S., Miglio U., Paganotti A., Veggiani C. 2009; Detection, distribution, and pathologic significance of BK virus strains isolated from patients with kidney transplants, with and without polyomavirus-associated nephropathy. Arch Pathol Lab Med 133:766–774[PubMed]
     [Google Scholar]
  13. Boldorini R., Allegrini S., Miglio U., Paganotti A., Cocca N., Zaffaroni M., Riboni F., Monga G., Viscidi R. 2011; Serological evidence of vertical transmission of JC and BK polyomaviruses in humans. J Gen Virol 92:1044–1050 [View Article][PubMed]
     [Google Scholar]
  14. Bratt G., Hammarin A. L., Grandien M., Hedquist B. G., Nennesmo I., Sundelin B., Seregarde S. 1999; BK virus as the cause of meningoencephalitis, retinitis and nephritis in a patient with AIDS. AIDS 13:1071–1075 [View Article][PubMed]
     [Google Scholar]
  15. Broekema N. M., Abend J. R., Bennett S. M., Butel J. S., Vanchiere J. A., Imperiale M. J. 2010; A system for the analysis of BKV non-coding control regions: application to clinical isolates from an HIV/AIDS patient. Virology 407:368–373 [View Article][PubMed]
     [Google Scholar]
  16. Cabrejo L., Diop M., Blohorn-Sense A., Mihout B. 2005; [Progressive BK virus associated multifocal leukoencephalopathy in an immunocompromised patient treated with corticosteroids]. Rev Neurol (Paris) 161:326–330 [View Article][PubMed]
     [Google Scholar]
  17. Carr M. J., McCormack G. P., Mutton K. J., Crowley B. 2006; Unique BK virus non-coding control region (NCCR) variants in hematopoietic stem cell transplant recipients with and without hemorrhagic cystitis. J Med Virol 78:485–493 [View Article][PubMed]
     [Google Scholar]
  18. Casas I., Tenorio A., Echevarría J. M., Klapper P. E., Cleator G. M. 1997; Detection of enteroviral RNA and specific DNA of herpesviruses by multiplex genome amplification. J Virol Methods 66:39–50 [View Article][PubMed]
     [Google Scholar]
  19. Chang D., Wang M., Ou W. C., Lee M. S., Ho H. N., Tsai R. T. 1996; Genotypes of human polyomaviruses in urine samples of pregnant women in Taiwan. J Med Virol 48:95–101 [View Article][PubMed]
     [Google Scholar]
  20. De Mattei M., Martini F., Corallini A., Gerosa M., Scotlandi K., Carinci P., Barbanti-Brodano G., Tognon M. 1995; High incidence of BK virus large-T-antigen-coding sequences in normal human tissues and tumors of different histotypes. Int J Cancer 61:756–760 [View Article][PubMed]
     [Google Scholar]
  21. Dörries K., Vogel E., Günther S., Czub S. 1994; Infection of human polyomaviruses JC and BK in peripheral blood leukocytes from immunocompetent individuals. Virology 198:59–70 [View Article][PubMed]
     [Google Scholar]
  22. Dugan A. S., Gasparovic M. L., Tsomaia N., Mierke D. F., O’Hara B. A., Manley K., Atwood W. J. 2007; Identification of amino acid residues in BK virus VP1 that are critical for viability and growth. J Virol 81:11798–11808 [View Article][PubMed]
     [Google Scholar]
  23. Egli A., Infanti L., Dumoulin A., Buser A., Samaridis J., Stebler C., Gosert R., Hirsch H. H. 2009; Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. J Infect Dis 199:837–846 [View Article][PubMed]
     [Google Scholar]
  24. Elsner C., Dörries K. 1992; Evidence of human polyomavirus BK and JC infection in normal brain tissue. Virology 191:72–80 [View Article][PubMed]
     [Google Scholar]
  25. Fedele C. G., Ciardi M., Delia S., Echevarria J. M., Tenorio A. 1999; Multiplex polymerase chain reaction for the simultaneous detection and typing of polyomavirus JC, BK and SV40 DNA in clinical samples. J Virol Methods 82:137–144 [View Article][PubMed]
     [Google Scholar]
  26. Feng H., Shuda M., Chang Y., Moore P. S. 2008; Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319:1096–1100 [View Article][PubMed]
     [Google Scholar]
  27. Ferrari A., Luppi M., Marasca R., Potenza L., Morselli M., Volzone F., Santachiara R., Forghieri F., Barozzi P., Torelli G. 2008; BK virus infection and neurologic dysfunctions in a patient with lymphoma treated with chemotherapy and rituximab. Eur J Haematol 81:244–245 [View Article][PubMed]
     [Google Scholar]
  28. Flaegstad T., Sundsfjord A., Arthur R. R., Pedersen M., Traavik T., Subramani S. 1991; Amplification and sequencing of the control regions of BK and JC virus from human urine by polymerase chain reaction. Virology 180:553–560 [View Article][PubMed]
     [Google Scholar]
  29. Friedman D. P., Flanders A. E. 2006; MR imaging of BK virus encephalitis. AJNR Am J Neuroradiol 27:1016–1018[PubMed]
     [Google Scholar]
  30. Garavelli P. L., Boldorini R. 2002; [BK virus encephalitis in an HIV-seropositive patient. Preliminary data]. Recenti Prog Med 93:247[PubMed]
     [Google Scholar]
  31. Gaynor A. M., Nissen M. D., Whiley D. M., Mackay I. M., Lambert S. B., Wu G., Brennan D. C., Storch G. A., Sloots T. P., Wang D. 2007; Identification of a novel polyomavirus from patients with acute respiratory tract infections. PLoS Pathog 3:e64 [View Article][PubMed]
     [Google Scholar]
  32. Gosert R., Rinaldo C. H., Funk G. A., Egli A., Ramos E., Drachenberg C. B., Hirsch H. H. 2008; Polyomavirus BK with rearranged noncoding control region emerge in vivo in renal transplant patients and increase viral replication and cytopathology. J Exp Med 205:841–852 [View Article][PubMed]
     [Google Scholar]
  33. Hammarin A. L., Bogdanovic G., Svedhem V., Pirskanen R., Morfeldt L., Grandien M. 1996; Analysis of PCR as a tool for detection of JC virus DNA in cerebrospinal fluid for diagnosis of progressive multifocal leukoencephalopathy. J Clin Microbiol 34:2929–2932[PubMed]
     [Google Scholar]
  34. Hedquist B. G., Bratt G., Hammarin A. L., Grandien M., Nennesmo I., Sundelin B., Seregard S. 1999; Identification of BK virus in a patient with acquired immune deficiency syndrome and bilateral atypical retinitis. Ophthalmology 106:129–132 [View Article][PubMed]
     [Google Scholar]
  35. Hirsch H. H., Steiger J. 2003; Polyomavirus BK. Lancet Infect Dis 3:611–623 [View Article][PubMed]
     [Google Scholar]
  36. Hix J. K., Braun W. E., Isada C. M. 2004; Delirium in a renal transplant recipient associated with BK virus in the cerebrospinal fluid. Transplantation 78:1407–1408 [View Article][PubMed]
     [Google Scholar]
  37. Johannessen M., Myhre M. R., Dragset M., Tümmler C., Moens U. 2008; Phosphorylation of human polyomavirus BK agnoprotein at Ser-11 is mediated by PKC and has an important regulative function. Virology 379:97–109 [View Article][PubMed]
     [Google Scholar]
  38. Jørgensen G. E., Hammarin A. L., Bratt G., Grandien M., Flaegstad T., Johnsen J. I. 2003; Identification of a unique BK virus variant in the CNS of a patient with AIDS. J Med Virol 70:14–19 [View Article][PubMed]
     [Google Scholar]
  39. Kean J. M., Rao S., Wang M., Garcea R. L. 2009; Seroepidemiology of human polyomaviruses. PLoS Pathog 5:e1000363 [View Article][PubMed]
     [Google Scholar]
  40. Kinnaird A. N., Anstead G. M. 2010; Hemorrhagic cystitis and possible neurologic disease from BK virus infection in a patient with AIDS. Infection 38:124–127 [View Article][PubMed]
     [Google Scholar]
  41. Lesprit P., Chaline-Lehmann D., Authier F. J., Ponnelle T., Gray F., Levy Y. 2001; BK virus encephalitis in a patient with AIDS and lymphoma. AIDS 15:1196–1199 [View Article][PubMed]
     [Google Scholar]
  42. Librado P., Rozas J. 2009; DnaSP v5: a software for comprehensive analysis of DNA polymorphism data. Bioinformatics 25:1451–1452 [View Article][PubMed]
     [Google Scholar]
  43. Lopes da Silva R. 2011a; BK virus neurotropism. J Infect Public Health 4:103–104 [View Article][PubMed]
     [Google Scholar]
  44. Lopes da Silva R. 2011b; Polyoma BK virus: an emerging opportunistic infectious agent of the human central nervous system. Braz J Infect Dis 15:276–284[PubMed] [CrossRef]
     [Google Scholar]
  45. Lopes da Silva R., Ferreira I., Teixeira G., Cordeiro D., Mafra M., Costa I., Bravo Marques J. M., Abecasis M. 2011; BK virus encephalitis with thrombotic microangiopathy in an allogeneic hematopoietic stem cell transplant recipient. Transpl Infect Dis 13:161–167 [View Article][PubMed]
     [Google Scholar]
  46. Markowitz R. B., Dynan W. S. 1988; Binding of cellular proteins to the regulatory region of BK virus DNA. J Virol 62:3388–3398[PubMed]
     [Google Scholar]
  47. Markowitz R. B., Tolbert S., Dynan W. S. 1990; Promoter evolution in BK virus: functional elements are created at sequence junctions. J Virol 64:2411–2415[PubMed]
     [Google Scholar]
  48. Markowitz R. B., Eaton B. A., Kubik M. F., Latorra D., McGregor J. A., Dynan W. S. 1991; BK virus and JC virus shed during pregnancy have predominantly archetypal regulatory regions. J Virol 65:4515–4519[PubMed]
     [Google Scholar]
  49. Marshall L. J., Major E. O. 2010; Molecular regulation of JC virus tropism: insights into potential therapeutic targets for progressive multifocal leukoencephalopathy. J Neuroimmune Pharmacol 5:404–417 [View Article][PubMed]
     [Google Scholar]
  50. Moens U., Johannessen M. 2008; Human polyomaviruses and cancer: expanding repertoire. J Dtsch Dermatol Ges 6:704–708 [View Article][PubMed]
     [Google Scholar]
  51. Moens U., Van Ghelue M. 2005; Polymorphism in the genome of non-passaged human polyomavirus BK: implications for cell tropism and the pathological role of the virus. Virology 331:209–231 [View Article][PubMed]
     [Google Scholar]
  52. Moens U., Subramaniam N., Johansen B., Johansen T., Traavik T. 1994; A steroid hormone response unit in the late leader of the noncoding control region of the human polyomavirus BK confers enhanced host cell permissivity. J Virol 68:2398–2408[PubMed]
     [Google Scholar]
  53. Moens U., Johansen T., Johnsen J. I., Seternes O. M., Traavik T. 1995; Noncoding control region of naturally occurring BK virus variants: sequence comparison and functional analysis. Virus Genes 10:261–275 [View Article][PubMed]
     [Google Scholar]
  54. Olsen G. H., Andresen P. A., Hilmarsen H. T., Bjørang O., Scott H., Midtvedt K., Rinaldo C. H. 2006; Genetic variability in BK virus regulatory regions in urine and kidney biopsies from renal-transplant patients. J Med Virol 78:384–393 [View Article][PubMed]
     [Google Scholar]
  55. Padgett B. L., Zurhein G. M., Walker D. L., Eckroade R. J., Dessel B. H. 1971; Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet 1:1257–1260 [View Article][PubMed]
     [Google Scholar]
  56. Pfister L. A., Letvin N. L., Koralnik I. J. 2001; JC virus regulatory region tandem repeats in plasma and central nervous system isolates correlate with poor clinical outcome in patients with progressive multifocal leukoencephalopathy. J Virol 75:5672–5676 [View Article][PubMed]
     [Google Scholar]
  57. Randhawa P., Zygmunt D., Shapiro R., Vats A., Weck K., Swalsky P., Finkelstein S. 2003; Viral regulatory region sequence variations in kidney tissue obtained from patients with BK virus nephropathy. Kidney Int 64:743–747 [View Article][PubMed]
     [Google Scholar]
  58. Reploeg M. D., Storch G. A., Clifford D. B. 2001; BK virus: a clinical review. Clin Infect Dis 33:191–202 [View Article][PubMed]
     [Google Scholar]
  59. Ribeiro T., Fleury M. J., Granieri E., Castellazzi M., Martini F., Mazzoni E., Coursaget P., Tognon M. 2010; Investigation of the prevalence of antibodies against neurotropic polyomaviruses BK, JC and SV40 in sera from patients affected by multiple sclerosis. Neurol Sci 31:517–521 [View Article][PubMed]
     [Google Scholar]
  60. Rubinstein R., Harley E. H. 1989; BK virus DNA cloned directly from human urine confirms an archetypal structure for the transcriptional control region. Virus Genes 2:157–165 [View Article][PubMed]
     [Google Scholar]
  61. Rubinstein R., Schoonakker B. C., Harley E. H. 1991; Recurring theme of changes in the transcriptional control region of BK virus during adaptation to cell culture. J Virol 65:1600–1604[PubMed]
     [Google Scholar]
  62. Ryschkewitsch C., Jensen P., Hou J., Fahle G., Fischer S., Major E. O. 2004; Comparison of PCR-Southern hybridization and quantitative real-time PCR for the detection of JC and BK viral nucleotide sequences in urine and cerebrospinal fluid. J Virol Methods 121:217–221 [View Article][PubMed]
     [Google Scholar]
  63. Sabath B. F., Major E. O. 2002; Traffic of JC virus from sites of initial infection to the brain: the path to progressive multifocal leukoencephalopathy. J Infect Dis 186:Suppl. 2S180–S186 [View Article][PubMed]
     [Google Scholar]
  64. Schowalter R. M., Pastrana D. V., Pumphrey K. A., Moyer A. L., Buck C. B. 2010; Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin. Cell Host Microbe 7:509–515 [View Article][PubMed]
     [Google Scholar]
  65. Scuda N., Hofmann J., Calvignac-Spencer S., Ruprecht K., Liman P., Kühn J., Hengel H., Ehlers B. 2011; A novel human polyomavirus closely related to the African green monkey-derived lymphotropic polyomavirus. J Virol 85:4586–4590 [View Article][PubMed]
     [Google Scholar]
  66. Seif I., Khoury G., Dhar R. 1979; The genome of human papovavirus BKV. Cell 18:963–977 [View Article][PubMed]
     [Google Scholar]
  67. Sharma P. M., Gupta G., Vats A., Shapiro R., Randhawa P. S. 2007; Polyomavirus BK non-coding control region rearrangements in health and disease. J Med Virol 79:1199–1207 [View Article][PubMed]
     [Google Scholar]
  68. Stoner G. L., Alappan R., Jobes D. V., Ryschkewitsch C. F., Landry M. L. 2002; BK virus regulatory region rearrangements in brain and cerebrospinal fluid from a leukemia patient with tubulointerstitial nephritis and meningoencephalitis. Am J Kidney Dis 39:1102–1112 [View Article][PubMed]
     [Google Scholar]
  69. Sugimoto C., Hara K., Taguchi F., Yogo Y. 1989; Growth efficiency of naturally occurring BK virus variants in vivo and in vitro. J Virol 63:3195–3199[PubMed]
     [Google Scholar]
  70. Sundsfjord A., Johansen T., Flaegstad T., Moens U., Villand P., Subramani S., Traavik T. 1990; At least two types of control regions can be found among naturally occurring BK virus strains. J Virol 64:3864–3871[PubMed]
     [Google Scholar]
  71. Sundsfjord A., Spein A. R., Lucht E., Flaegstad T., Seternes O. M., Traavik T. 1994; Detection of BK virus DNA in nasopharyngeal aspirates from children with respiratory infections but not in saliva from immunodeficient and immunocompetent adult patients. J Clin Microbiol 32:1390–1394[PubMed]
     [Google Scholar]
  72. Sundsfjord A., Osei A., Rosenqvist H., Van Ghelue M., Silsand Y., Haga H. J., Rekvig O. P., Moens U. 1999; BK and JC viruses in patients with systemic lupus erythematosus: prevalent and persistent BK viruria, sequence stability of the viral regulatory regions, and nondetectable viremia. J Infect Dis 180:1–9 [View Article][PubMed]
     [Google Scholar]
  73. Tornatore C., Berger J. R., Houff S. A., Curfman B., Meyers K., Winfield D., Major E. O. 1992; Detection of JC virus DNA in peripheral lymphocytes from patients with and without progressive multifocal leukoencephalopathy. Ann Neurol 31:454–462 [View Article][PubMed]
     [Google Scholar]
  74. Tremolada S., Delbue S., Larocca S., Carloni C., Elia F., Khalili K., Gordon J., Ferrante P. 2010; Polymorphisms of the BK virus subtypes and their influence on viral in vitro growth efficiency. Virus Res 149:190–196 [View Article][PubMed]
     [Google Scholar]
  75. Vago L., Cinque P., Sala E., Nebuloni M., Caldarelli R., Racca S., Ferrante P., Trabottoni G., Costanzi G. 1996; JCV-DNA and BKV-DNA in the CNS tissue and CSF of AIDS patients and normal subjects. Study of 41 cases and review of the literature. J Acquir Immune Defic Syndr Hum Retrovirol 12:139–146 [View Article][PubMed]
     [Google Scholar]
  76. Vallbracht A., Löhler J., Gossmann J., Glück T., Petersen D., Gerth H. J., Gencic M., Dörries K. 1993; Disseminated BK type polyomavirus infection in an AIDS patient associated with central nervous system disease. Am J Pathol 143:29–39[PubMed]
     [Google Scholar]
  77. van der Meijden E., Janssens R. W., Lauber C., Bouwes Bavinck J. N., Gorbalenya A. E., Feltkamp M. C. 2010; Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient. PLoS Pathog 6:e1001024 [View Article][PubMed]
     [Google Scholar]
  78. Vidal J. E., Fink M. C., Cedeno-Laurent F., Delbue S., Ferrante P., Dauar R. F., Filho F. B., Nogueira R. S., Calore E. E. other authors 2007; BK virus associated meningoencephalitis in an AIDS patient treated with HAART. AIDS Res Ther 4:13 [View Article][PubMed]
     [Google Scholar]
  79. Voltz R., Jäger G., Seelos K., Fuhry L., Hohlfeld R. 1996; BK virus encephalitis in an immunocompetent patient. Arch Neurol 53:101–103 [View Article][PubMed]
     [Google Scholar]
  80. White M. K., Khalili K. 2011; Pathogenesis of progressive multifocal leukoencephalopathy–revisited. J Infect Dis 203:578–586 [View Article][PubMed]
     [Google Scholar]
  81. Zhong S., Zheng H. Y., Suzuki M., Chen Q., Ikegaya H., Aoki N., Usuku S., Kobayashi N., Nukuzuma S. other authors 2007; Age-related urinary excretion of BK polyomavirus by nonimmunocompromised individuals. J Clin Microbiol 45:193–198 [View Article][PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.042143-0
Loading
BK polyomavirus with archetypal and rearranged non-coding control regions is present in cerebrospinal fluids from patients with neurological complications
J. Gen. Virol. 93, 1780 (2012); https://doi.org/10.1099/vir.0.042143-0
/content/journal/jgv/10.1099/vir.0.042143-0
/content/journal/jgv/10.1099/vir.0.042143-0
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error