Top

Published in:

01-02-2019 | Original Investigation

Role of pentamer complex-specific and IgG subclass 3 antibodies in HCMV hyperimmunoglobulin and standard intravenous IgG preparations

Authors: Matthias Stefan Schampera, Jose Arellano-Galindo, Karl Oliver Kagan, Stuart P. Adler, Gerhard Jahn, Klaus Hamprecht

Published in: Medical Microbiology and Immunology | Issue 1/2019

Abstract

Background

HCMV hyperimmunoglobulin-preparations (HIG) contain high concentrations of HCMV-specific IgG. The reduced maternofetal-HCMV-transmission rate of IgG may be due to HCMV-specific neutralizing antibodies against the HCMV pentameric complex (PC). In contrast to HIG, standard intravenous immunoglobulin (IVIG) may have more neutralization (NT) capacity than HIG due to higher IgG subclass 3 levels (Planitzer et al., 2011).

Methods

We investigated the HCMV-specific NT-capacity of HIG Cytotect^®, using a recombinant pentameric complex (gHgLUL128-131A) for specific antibody-depletion. We used a modified UL130-peptide (TANQNPSPPWSKLTYSKPH) based on original-sequence of Saccoccio et al. (Vaccine 29(15):2705–2711, 2011) (SWSTLTANQNPSPPWSKLTY) as neutralization target. Both UL130-peptides and the PC were bound via sixfold HisTag and anti-HisTag mAbs to magnetic beads to deplete HCMV-specific IgGs from HIG (Cytotect^®). Modifying this depletion strategy, we analyzed the role of IgG subclass 3 in both HIG and IVIG.

Results

After CMV IgG-normalization of HIG and IVIG, we found a significant trend towards a decrease (16%) of neutralization-capacity for the UL130 TAN-peptide, but not for the original UL130 SWS-peptide. However, highly significant loss of NT-capacity could be only observed by PC depletion (42%). The IgG subclass 3 depletion revealed no significant reduction of NT-capacity in both HIG and IVIG.

Conclusion

Via specific antibody depletion, we could demonstrate that pentameric complex-specific antibodies are present in HIG and bind to the recombinant PC resulting in a highly significant reduction of NT-capacity compared to the UL130 TAN-and SWS-peptides. We could not confirm the functional role of IgG subclass 3 neutralizing antibodies in IgG-preparations.

Available only for authorised users

Picone O, Vauloup-Fellous C, Cordier AG, Guitton S, Senat MV, Fuchs F, Ayoubi JM, Grangeot Keros L, Benachi A (2013) A series of 238 cytomegalovirus primary infections during pregnancy: description and outcome. Prenat Diagn 33(8):751–758CrossRef

Pass RF (2009) Development and evidence for efficacy of HCMV glycoprotein B vaccine with MF59 adjuvant J. Clin Virol 46:73–76CrossRef

Connolly SA, Jackson JO, Jardetzky TS, Longnecker R (2011) Fusing structure and function: a structural view of the herpesvirus entry machinery. Nat Rev Microbiol 9:369–381CrossRefPubMedCentralPubMed

Eisenberg RJ, Atanasiu D, Cairns TM, Gallagher JR, Krummenacher C et al (2012) Herpes virus fusion and entry: a story with many characters. Viruses 4:800–832CrossRefPubMedCentralPubMed

Ciferri C, Chandramouli S, Donnarumma D, Nikitin PA, Cianfrocco MA, Gerrein R, Feire AL, Barnett SW1, Lilja AE, Rappuoli R, Norais N, Settembre EC, Carfi A (2015) Structural and biochemical studies of HCMV gH/gL/gO and Pentamer reveal mutually exclusive cell entry complexes. Proc Natl Acad Sci USA 112(6):1767–1772CrossRefPubMed

Stegmann C, Abdellatif ME, Laib Sampaio K, Walther P, Sinzger C (2016) Importance of highly conserved peptide sites of human cytomegalovirus gO for formation of the gH/gL/gO complex. J Virol. 91(1):e01339-16CrossRefPubMedCentralPubMed

Lemmermann NA, Krmpotic A, Podlech J, Brizic I, Prager A, Adler H, Karbach A, Wu Y, Jonjic S, Reddehase MJ, Adler B (2015) Non-redundant and redundant roles of cytomegalovirus gH/gL complexes in host organ entry and intra-tissue spread. PLoS Pathog 11(2):e1004640CrossRefPubMedCentralPubMed

Vanarsdall AL, Chase MC, Johnson DC (2011) Human cytomegalovirus glycoprotein gO complexes with gH/gL, promoting interference with viral entry into human fibroblasts but not entry into epithelial cells. J Virol 85:11638–11645CrossRefPubMedCentralPubMed

Adler B, Scrivano L, Ruzcics Z, Rupp B, Sinzger C, Koszinowski U (2006) Role of human cytomegalovirus UL131A in cell type-specific virus entry and release. J Gen Virol 87(Pt 9):2451–2460CrossRefPubMed

10.

Hahn G, Revello MG, Patrone M, Percivalle E, Campanini G, Sarasini A, Wagner M, Gallina A, Milanesi G, Koszinowski U, Baldanti F, Gerna G (2004) Human cytomegalovirus UL131-128 genes are indispensable for virus growth in endothelial cells and virus transfer to leukocytes. J Virol 78(18):10023–10033CrossRefPubMedCentralPubMed

11.

Gerna G, Percivalle E, Lilleri D, Lozza L, Fornara C et al (2005) Dendritic-cell infection by human cytomegalovirus is restricted to strains carrying functional UL131–128 genes and mediates efficient viral antigen presentation to CD8+ T cells. J Gen Virol 86:275–284. PMIDCrossRefPubMed

12.

Wang D, Shenk T (2005) Human cytomegalovirus virion protein complex required for epithelial and endothelial cell tropism. Proc Natl Acad Sci USA 102(50):18153–18158CrossRefPubMed

13.

Sinzger C, Eberhardt K, Cavignac Y, Weinstock C, Kessler T et al (2006) Macrophage cultures are susceptible to lytic productive infection by endothelial-cell-propagated human cytomegalovirus strains and present viral IE1 protein to CD4 + T cells despite late downregulation of MHC class II molecules. J Gen Virol 87:1853–1862CrossRefPubMed

14.

Fouts AE, Chan P, Stephan JP, Vandlen R, Feierbach B (2012) Antibodies against the gH/gL/UL128/UL130/UL131 complex comprise the majority of the anti-cytomegalovirus (anti-CMV) neutralizing antibody response in CMV hyperimmune globulin. J Virol 86(13):7444–7447CrossRefPubMedCentralPubMed

15.

Ryckman BJ, Rainish BL, Chase MC, Borton JA, Nelson JA, Jarvis MA, Johnson DC (2008) Characterization of the human cytomegalovirus gH/gL/UL128-131 complex that mediates entry into epithelial and endothelial cells. J Virol 82(1):60–70CrossRefPubMed

16.

Ha S, Li F, Troutman MC, Freed DC, Tang A, Loughney JW, Wang D, Wang IM, Vlasak J, Nickle DC, Rustandi RR, Hamm M, DePhillips PA, Zhang N, McLellan JS, Zhu H, Adler SP, McVoy MA, An Z, Fu TM (2017) Neutralization of diverse human cytomegalovirus strains conferred by antibodies targeting viral gH/gL/pUL128-131 pentameric complex. J Virol 91(7):e02033-16. https://doi.org/10.1128/JVI.02033-16 CrossRefPubMedCentralPubMed

17.

Zydek M, Petitt M, Fang-Hoover J, Adler B, Kauvar LM, Pereira L, Tabata T (2014) HCMV infection of human trophoblast progenitor cells of the placenta is neutralized by a human monoclonal antibody to glycoprotein B and not by antibodies to the pentamer complex. Viruses 6(3):1346–1364CrossRefPubMedCentralPubMed

18.

Lilleri D, Kabanova A, Revello MG, Percivalle E, Sarasini A et al (2013) Fetal human cytomegalovirus transmission correlates with delayed maternal antibodies to gH/gL/pUL128-130-131 complex during primary infection. PLoS One 8:e59863CrossRefPubMedCentralPubMed

19.

Nigro G, Adler SP, La TR, Best AM (2005) Passive immunization during pregnancy for congenital cytomegalovirus infection. Engl J Med 353:1350–1362CrossRef

20.

Visentin S, Manara R, Milanese L, Da Roit A, Forner G, Salviato E, Citton V, Magno FM, Orzan E, Morando C, Cusinato R, Mengoli C, Palu G, Ermani M, Rinaldi R, Cosmi E, Gussetti N (2012) Early primary cytomegalovirus infection in pregnancy: maternal hyperimmunoglobulin therapy improves outcomes among infants at 1 year of age. Clin Infect Dis 55(4):497–503CrossRefPubMed

21.

Buxmann H, Stackelberg OM, Schlößer RL, Enders G, Gonser M, Meyer-Wittkopf M, Hamprecht K, Enders M (2012) Use of cytomegalovirus hyperimmunoglobulin for prevention of congenital cytomegalovirus disease: a retrospective analysis. J Perinat Med 40(4):439–446PubMed

22.

Revello MG, Lazzarotto T, Guerra B, Spinillo A, Ferrazzi E, Kustermann A, Guaschino S, Vergani P, Todros T, Frusca T, Arossa A, Furione M, Rognoni V, Rizzo N, Gabrielli L, Klersy C, Gerna G, CHIP Study Group (2014) A randomized trial of hyperimmune globulin to prevent congenital. N Engl J Med 370(14):1316–1326CrossRef

23.

Rawlinson WD, Boppana SB, Fowler KB, Kimberlin DW, Lazzarotto T, Alain S, Daly K, Doutré S, Gibson L, Giles ML, Greenlee J, Hamilton ST, Harrison GJ, Hui L, Jones CA, Palasanthiran P, Schleiss MR, Shand MW, van Zuylen WJ (2017) Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy. Lancet Infect Dis 17(6):e177–e188CrossRefPubMed

24.

Kagan KO, Enders M, Schampera MS, Baeumel E, Hoopmann M, Geipel A, Berg C, Goelz R, De Catte L, Wallwiener D, Brucker S, Adler SP, Jahn G, Hamprecht K (2018) Prevention of maternal-fetal transmission of CMV by hyperimmunoglobulin (HIG) administered after a primary maternal CMV infection in early gestation. Ultrasound Obstet Gynecol. https://doi.org/10.1002/uog.19164 CrossRef

25.

Schampera MS, Schweinzer K, Abele H, Kagan KO, Klein R, Rettig I, Jahn G, Hamprecht K (2017) Comparison of cytomegalovirus (CMV)-specific neutralization capacity of hyperimmunoglobulin (HIG) versus standard intravenous immunoglobulin (IVIG) preparations: impact of CMV IgG normalization. J Clin Virol 90:40–45CrossRefPubMed

26.

Planitzer CB, Saemann MD, Gajek H, Farcet MR, Kreil TR (2011) Cytomegalovirus neutralization by hyperimmune and standard intravenous immunoglobulin preparations. Transplantation 92(3):267–270. https://doi.org/10.1097/TP.0b013e318224115e CrossRefPubMed

27.

Gupta CK, Leszczynski J, Gupta RK et al (1996) IgG subclass antibodies to human cytomegalovirus (CMV) in normal human plasma samples and immune globulins and their neutralizing activities. Biologicals 24:117CrossRefPubMed

28.

Saccoccio FM, Sauer AL, Cui X, Armstrong AE, Habib el-SE, Johnson DC, Ryckman BJ, Klingelhutz AJ, Adler SP, McVoy MA (2011) Peptides from cytomegalovirus UL130 and UL131 proteins induce high titer antibodies that block viral entry into mucosal epithelial cells. Vaccine 29(15):2705–2711CrossRefPubMedCentralPubMed

29.

Yang X, Yu X (2009) An introduction to epitope prediction methods and software. Rev Med Virol 19(2):77–96CrossRefPubMed

30.

Jespersen MC, Peters B, Nielsen M, Marcatili P (2017) BepiPred-2.0: improving sequence-based B-cell epitope prediction using conformational epitopes. Nucleic Acids Res 45(W1):w24–w29CrossRefPubMedCentralPubMed

31.

Yao B, Zhang L, Liang S, Zhang C (2012) SVMTriP: A method to predict antigenic epitopes using support vector machine to integrate tri-peptide similarity and propensity. PLoS One 7(9):e45152CrossRefPubMedCentralPubMed

32.

Saha S, Raghava GPS (2004) BcePred: prediction of continuous B-cell epitopes in antigenic sequences using physico-chemical properties, vol 3239. ICARIS, LNCS, Springer, New York, pp 197–204

33.

Zhang Y (2008) I-TASSER server for protein 3D structure prediction. BMC Bioinform 9(1):40CrossRef

34.

Germer M, Herbener P, Schüttrumpf J (2016) Functional properties of human cytomegalovirus hyperimmunoglobulin and standard immunoglobulin preparations. Ann Transpl 21:558–564CrossRef

35.

Wang X, Xu Y, Scott DE, Murata H, Struble EB (2017) Binding and neutralizing anti-cytomegalovirus activities in immune globulin products. Biologicals 50:35–41CrossRefPubMed

36.

Chandramouli S, Malito E, Nguyen T, Luisi K, Donnarumma D, Xing Y, Norais N, Yu D, Carfi A (2017) Structural basis for potent antibody-mediated neutralization of human cytomegalovirus. Sci Immunol 2(12):eaan1457CrossRefPubMed

37.

Cui X, Meza BP, Adler SP, McVoy MA (2008) Cytomegalovirus vaccines fail to induce epithelial entry neutralizing antibodies comparable to natural infection. Vaccine 26:5760–5766CrossRefPubMedCentralPubMed

38.

Loughney JW, Rustandi RR, Wang D, Troutman MC, Dick LW Jr, Li G, Liu Z, Li F, Freed DC, Price CE, Hoang VM, Culp TD, DePhillips PA, Fu TM, Ha S (2015) Soluble human cytomegalovirus gH/gL/pUL128-131 pentameric complex, but not gH/gL, inhibits viral entry to epithelial cells and presents dominant native neutralizing epitopes. J Biol Chem 290(26):15985–15995CrossRefPubMedCentralPubMed

39.

Macagno A, Bernasconi NL, Vanzetta F, Dander E, Sarasini A, Revello MG, Gerna G, Sallusto F, Lanzavecchia A (2010) Isolation of human monoclonal antibodies that potently neutralize human cytomegalovirus infection by targeting different epitopes on the gH/gL/UL128-131A complex. J Virol 84(2):1005–1013CrossRefPubMed

40.

Gerna G, Percivalle E, Perez L, Lanzavecchia A, Lilleri D (2016) Monoclonal antibodies to different components of the human cytomegalovirus (HCMV) pentamer gH/gL/pUL128L and trimer gH/gL/gO as well as antibodies elicited during primary HCMV Infection prevent epithelial cell syncytium formation. J Virol 90(14):6216–6223CrossRefPubMedCentralPubMed

41.

Ha S, Li F, Troutman MC, Freed DC, Tang A, Loughney JW, Wang D, Wang I-Ming, Vlasak J, Nickle DC, Rustandi RR, Hamm M, DePhillips PA, Zhang N, McLellan JS, Zhu H, Adler SP, McVoy MA, Zhiqiang AN, Tong-Ming FU (2017) Neutralization of diverse human cytomegalovirus strains conferred by antibodies targeting viral gH/gL/pUL128-131 pentameric complex. J Virol 91(7):JVI-02033CrossRef

42.

Hofmann I, Wen Y, Ciferri C, Schulze A, Fühner V, Leong M, Gerber A, Gerrein R, Nandi A, Lilja AE, Carfi A, Laux H (2015) Expression of the human cytomegalovirus pentamer complex for vaccine use in a CHO system. Biotechnol Bioeng 112(12):2505–2515CrossRefPubMed

43.

Hamilton ST, van Zuylen W, Shand A, Scott GM, Naing Z, Hall B, Craig ME, Rawlinson WD (2014) Prevention of congenital cytomegalovirus complications by maternal and neonatal treatments: a systematic review. Rev Med Virol. (6):420–433

44.

Hamprecht K, Kagan KO, Goelz R (2014) Comment on: a randomized trial of hyperimmune globulin to prevent congenital cytomegalovirus. N Engl J Med 370(26):2543CrossRefPubMed

45.

Gerna G, Revello MG, Baldanti F, Percivalle E, Lilleri D (2017) The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development. J Gen Virol 98(9):2215–2234CrossRefPubMed

Title: Role of pentamer complex-specific and IgG subclass 3 antibodies in HCMV hyperimmunoglobulin and standard intravenous IgG preparations
Authors: Matthias Stefan Schampera
Jose Arellano-Galindo
Karl Oliver Kagan
Stuart P. Adler
Gerhard Jahn
Klaus Hamprecht
Publication date: 01-02-2019
Publisher: Springer Berlin Heidelberg
Published in: Medical Microbiology and Immunology / Issue 1/2019
Print ISSN: 0300-8584
Electronic ISSN: 1432-1831
DOI: https://doi.org/10.1007/s00430-018-0558-x

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Role of pentamer complex-specific and IgG subclass 3 antibodies in HCMV hyperimmunoglobulin and standard intravenous IgG preparations

Abstract

Background

Methods

Results

Conclusion

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2019

Activation of brain endothelium by Escherichia coli K1 virulence factor cglD promotes polymorphonuclear leukocyte transendothelial migration

β-Glucan induces autophagy in dendritic cells and influences T-cell differentiation

Polymorphisms in the TGFB1 signal peptide influence human papillomavirus infection and development of cervical lesions

Intranasal co-administration of recombinant active fragment of Zonula occludens toxin and truncated recombinant EspB triggers potent systemic, mucosal immune responses and reduces span of E. coli O157:H7 fecal shedding in BALB/c mice

Chylous ascites, anti-interferon-gamma autoantibody, and angioimmunoblastic T-cell lymphoma: a rare but intriguing connection over Mycobacterium avium

Hepatitis C virus cell culture models: an encomium on basic research paving the road to therapy development

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page