An antibody response to human polyomavirus 15-mer peptides is highly abundant in healthy human subjects

Virology Journal

Luc Tritsmans³  Ellen Van Gulck²  Tom Van Loy¹  Tobias Verbeke⁴  Lieven J Stuyver¹ 

[1] Janssen Diagnostics, Turnhoutsebaan 30, Beerse, B-2340, Belgium;Janssen Infectious Disease –CREATe, Beerse, Belgium;Janssen R&D, Beerse, Belgium;Open Analytics, Antwerpen, Belgium

关键词: Pentapeptides epitopes;    Peptide microarray;    Human polyomaviruses;   

Others  :  1149694
DOI  :  10.1186/1743-422X-10-192

 received in 2013-03-18, accepted in 2013-06-04,  发布年份 2013

【 摘 要 】

Background

Human polyomaviruses (HPyV) infections cause mostly unapparent or mild primary infections, followed by lifelong nonpathogenic persistence. HPyV, and specifically JCPyV, are known to co-diverge with their host, implying a slow rate of viral evolution and a large timescale of virus/host co-existence. Recent bio-informatic reports showed a large level of peptide homology between JCPyV and the human proteome. In this study, the antibody response to PyV peptides is evaluated.

Methods

The in-silico analysis of the HPyV proteome was followed by peptide microarray serology. A HPyV-peptide microarray containing 4,284 peptides was designed and covered 10 polyomavirus proteomes. Plasma samples from 49 healthy subjects were tested against these peptides.

Results

In-silico analysis of all possible HPyV 5-mer amino acid sequences were compared to the human proteome, and 1,609 unique motifs are presented. Assuming a linear epitope being as small as a pentapeptide, on average 9.3% of the polyomavirus proteome is unique and could be recognized by the host as non-self. Small t Ag (stAg) contains a significantly higher percentage of unique pentapeptides. Experimental evidence for the presence of antibodies against HPyV 15-mer peptides in healthy subjects resulted in the following observations: i) antibody responses against stAg were significantly elevated, and against viral protein 2 (VP2) significantly reduced; and ii) there was a significant correlation between the increasing number of embedded unique HPyV penta-peptides and the increase in microarray fluorescent signal.

Conclusion

The anti-peptide HPyV-antibodies in healthy subjects are preferably directed against the penta-peptide derived unique fraction of the viral proteome.

【 授权许可】

   
2013 Stuyver et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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【 参考文献 】

• [1]Johne R, Buck CB, Allander T, Atwood WJ, Garcea RL, Imperiale MJ, Major EO, Ramqvist T, Norkin LC: Taxonomical developments in the family Polyomaviridae. Arch Virol 2012, 156:1627-1634.
• [2]Gaynor AM, Nissen MD, Whiley DM, Mackay IM, Lambert SB, Wu G, Brennan DC, Storch GA, Sloots TP, Wang D: Identification of a novel polyomavirus from patients with acute respiratory tract infections. PLoS Pathog 2007, 3:e64.
• [3]Allander T, Andreasson K, Gupta S, Bjerkner A, Bogdanovic G, Persson MA, Dalianis T, Ramqvist T, Andersson B: Identification of a third human polyomavirus. J Virol 2007, 81:4130-4136.
• [4]Feng H, Shuda M, Chang Y, Moore PS: Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008, 319:1096-1100.
• [5]van der Meijden E, Janssens RW, Lauber C, Bouwes Bavinck JN, Gorbalenya AE, Feltkamp MC: Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient. PLoS Pathog 2010, 6:e1001024.
• [6]Schowalter RM, Pastrana DV, Pumphrey KA, Moyer AL, Buck CB: Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin. Cell Host Microbe 2010, 7:509-515.
• [7]Scuda N, Hofmann J, Calvignac-Spencer S, Ruprecht K, Liman P, Kuhn J, Hengel H, Ehlers B: A novel human polyomavirus closely related to the african green monkey-derived lymphotropic polyomavirus. J Virol 2011, 85:4586-4590.
• [8]Buck CB, Phan GQ, Raiji MT, Murphy PM, McDermott DH, McBride AA: Complete genome sequence of a tenth human polyomavirus. J Virol 2012, 86:10887.
• [9]Siebrasse EA, Reyes A, Lim ES, Zhao G, Mkakosya RS, Manary MJ, Gordon JI, Wang D: Identification of MW Polyomavirus, a Novel Polyomavirus in Human Stool. J Virol 2012, 86:10321-10326.
• [10]Lim ES, Reyes A, Antonio M, Saha D, Ikumapayi UN, Adeyemi M, Stine OC, Skelton R, Brennan DC, Mkakosya RS, et al.: Discovery of STL polyomavirus, a polyomavirus of ancestral recombinant origin that encodes a unique T antigen by alternative splicing. Virology 2013, 436:295-303.
• [11]Korup S, Rietscher J, Calvignac-Spencer S, Trusch F, Hofmann J, Moens U, Sauer I, Voigt S, Schmuck R, Ehlers B: Identification of a novel human polyomavirus in organs of the gastrointestinal tract. PLoS One 2013, 8:e58021.
• [12]Corallini A, Mazzoni E, Taronna A, Manfrini M, Carandina G, Guerra G, Guaschino R, Vaniglia F, Magnani C, Casali F, et al.: Specific antibodies reacting with simian virus 40 capsid protein mimotopes in serum samples from healthy blood donors. Hum Immunol 2012, 73:502-510.
• [13]Bouvard V, Baan RA, Grosse Y, Lauby-Secretan B, El Ghissassi F, Benbrahim-Tallaa L, Guha N, Straif K: Carcinogenicity of malaria and of some polyomaviruses. Lancet Oncol 2012, 13:339-340.
• [14]Sauvage V, Foulongne V, Cheval J, Ar Gouilh M, Pariente K, Dereure O, Manuguerra JC, Richardson J, Lecuit M, Burguiere A, et al.: Human polyomavirus related to African green monkey lymphotropic polyomavirus. Emerg Infect Dis 2011, 17:1364-1370.
• [15]Kean JM, Rao S, Wang M, Garcea RL: Seroepidemiology of human polyomaviruses. PLoS Pathog 2009, 5:e1000363.
• [16]Viscidi RP, Clayman B: Serological cross reactivity between polyomavirus capsids. Adv Exp Med Biol 2006, 577:73-84.
• [17]Plavina T, Berman M, Njenga M, Crossman M, Lerner M, Gorelik L, Simon K, Schlain B, Subramanyam M: Multi-site analytical validation of an assay to detect anti-JCV antibodies in human serum and plasma. J Clin Virol 2012, 53:65-71.
• [18]Rollison DE, Helzlsouer KJ, Lee JH, Fulp W, Clipp S, Hoffman-Bolton JA, Giuliano AR, Platz EA, Viscidi RP: Prospective study of JC virus seroreactivity and the development of colorectal cancers and adenomas. Cancer Epidemiol Biomarkers Prev 2009, 18:1515-1523.
• [19]Bodaghi S, Comoli P, Bosch R, Azzi A, Gosert R, Leuenberger D, Ginevri F, Hirsch HH: Antibody responses to recombinant polyomavirus BK large T and VP1 proteins in young kidney transplant patients. J Clin Microbiol 2009, 47:2577-2585.
• [20]Hamilton RS, Gravell M, Major EO: Comparison of antibody titers determined by hemagglutination inhibition and enzyme immunoassay for JC virus and BK virus. J Clin Microbiol 2000, 38:105-109.
• [21]Antonsson A, Green AC, Mallitt KA, O'Rourke PK, Pawlita M, Waterboer T, Neale RE: Prevalence and stability of antibodies to the BK and JC polyomaviruses: a long-term longitudinal study of Australians. J Gen Virol 2010, 91:1849-1853.
• [22]Food-and-Drug-Administration: Anti- John Cunningham Virus (JCV) antibodies measured by Enzyme Linked Immunosorbent Assay (ELISA); 510(k) Number: K112394. http://www.accessdata.fda.gov/cdrh_docs/reviews/K112394.pdf webcite 2012
• [23]Moens U, Van Ghelue M, Song X, Ehlers B: Serological cross-reactivity between human polyomaviruses. Rev Med Virol 2013.
• [24]Agostini HT, Deckhut A, Jobes DV, Girones R, Schlunck G, Prost MG, Frias C, Perez-Trallero E, Ryschkewitsch CF, Stoner GL: Genotypes of JC virus in East, Central and Southwest Europe. J Gen Virol 2001, 82:1221-1331.
• [25]Sharp PM, Simmonds P: Evaluating the evidence for virus/host co-evolution. Curr Opin Virol 2011, 1:436-441.
• [26]Lucchese G: Confronting JC virus and Homo sapiens biological signatures. Front Biosci 2013, 18:716-724.
• [27]Buus S, Rockberg J, Forsstr Oumlm BO, Nilsson P, Uhlen M, Schafer-Nielsen C: High-resolution mapping of linear antibody epitopes using ultrahigh-density peptide microarrays. Mol Cell Proteomics 2012, 11:1790-1800.
• [28]Yohai VJ: High breakdown-point and high efficiency estimates for regression. The Annals of Statistics 1987, 15:642-665.
• [29]Koller M, Stahel WA: Sharpening Wald-type inference in robust regression for small samples. Computational Statistics and Data Analysis 2011, 55:2504-2515.
• [30]Khalili K, Sariyer IK, Safak M: Small tumor antigen of polyomaviruses: role in viral life cycle and cell transformation. J Cell Physiol 2008, 215:309-319.
• [31]Poletaev AB: The immunological homunculus (immunculus) in normal state and pathology. Biochemistry (Mosc) 2002, 67:600-608.
• [32]Madi A, Bransburg-Zabary S, Kenett DY, Ben-Jacob E, Cohen IR: The natural autoantibody repertoire in newborns and adults: a current overview. Adv Exp Med Biol 2012, 750:198-212.
• [33]Randhawa P, Viscidi R, Carter JJ, Galloway DA, Culp TD, Huang C, Ramaswami B, Christensen ND: Identification of species-specific and cross-reactive epitopes in human polyomavirus capsids using monoclonal antibodies. J Gen Virol 2009, 90:634-639.
• [34]Wang M, Tzeng TY, Fung CY, Ou WC, Tsai RT, Lin CK, Tsay GJ, Chang D: Human anti-JC virus serum reacts with native but not denatured JC virus major capsid protein VP1. J Virol Methods 1999, 78:171-176.
• [35]Gaseitsiwe S, Valentini D, Mahdavifar S, Reilly M, Ehrnst A, Maeurer M: Peptide microarray-based identification of Mycobacterium tuberculosis epitope binding to HLA-DRB1*0101, DRB1*1501, and DRB1*0401. Clin Vaccine Immunol 2010, 17:168-175.
• [36]Valentini D, Gaseitsiwe S, Maeurer M: Humoral 'reactome' profiles using peptide microarray chips. Trends Immunol 2010, 31:399-400.
• [37]Price JV, Tangsombatvisit S, Xu G, Yu J, Levy D, Baechler EC, Gozani O, Varma M, Utz PJ, Liu CL: On silico peptide microarrays for high-resolution mapping of antibody epitopes and diverse protein-protein interactions. Nat Med 2012, 9:1434-1440.
• [38]Andresen H, Grotzinger C, Zarse K, Kreuzer OJ, Ehrentreich-Forster E, Bier FF: Functional peptide microarrays for specific and sensitive antibody diagnostics. Proteomics 2006, 6:1376-1384.
• [39]Fernandez L, Chan WC, Egido M, Gomara MJ, Haro I: Synthetic peptides derived from an N-terminal domain of the E2 protein of GB virus C in the study of GBV-C/HIV-1 co-infection. J Pept Sci 2013, 18:326-335.
• [40]R-Core-Team: R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2012. http://www.r-project.org/ webcite
• [41]Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, et al.: Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 2004, 5:R80. BioMed Central Full Text
• [42]Pages H, Aboyoun P, Gentleman R, DebRoy S: Biostrings: String objects representing biological sequences, and matching algorithms. R package version 2241 2012
• [43]Hothorn T, Hornik K, van de Wiel MA, Zeileis A: Implementing a Class of Permutation Tests: The coin Package. J Stat Software 2008, 28:1-23.
• [44]Rousseeuw P, Croux C, Todorov V, Ruckstuhl A, Salibian-Barrera M, Verbeke T, Koller M, Maechler M: robustbase: Basic Robust Statistics. R package version 0.8-0. 2011. http://CRAN.R-project.org/package=robustbase webcite