Increased titers of neutralizing antibodies after immunization with both envelope proteins of the porcine endogenous retroviruses (PERVs)

Virology Journal

Christa-Maria Schmidt¹  Danny Kaulitz¹  Debora Mihica¹  Joachim Denner¹ 

[1] Center of HIV and Retrovirology, Robert Koch Institute, Nordufer 20, 13353, Berlin, Germany

关键词: Porcine Endogenous Retroviruses (PERV);    HIV-1;    Neutralizing antibodies;    Vaccine;   

Others  :  1153279
DOI  :  10.1186/1743-422X-9-260

 received in 2012-05-28, accepted in 2012-10-31,  发布年份 2012

【 摘 要 】

Despite enormous difficulties to induce antibodies neutralizing HIV-1, especially broadly neutralizing antibodies directed against the conserved membrane proximal external region (MPER) of the transmembrane envelope protein, such antibodies can be easily induced in the case of gammaretroviruses, among them the porcine endogenous retroviruses (PERVs). In addition to neutralizing antibodies directed against the transmembrane envelope protein p15E, neutralizing antibodies were also induced by immunization with the surface envelope protein gp70. PERVs represent a special risk for xenotransplantation using pig tissues or organs since they are integrated in the genome of all pigs and infect human cells and a vaccine may protect from transmission to the recipient. To investigate the effect of simultaneous immunization with both proteins in detail, a study was performed in hamsters. Gp70 and p15E of PERV were produced in E. coli, purified and used for immunization. All animals developed binding antibodies against the antigens used for immunization. Sera from animals immunized with p15E recognized epitopes in the MPER and the fusion peptide proximal region (FPPR) of p15E. One MPER epitope showed a sequence homology to an epitope in the MPER of gp41 of HIV-1 recognized by broadly neutralizing antibodies found in HIV infected individuals. Neutralizing antibodies were detected in all sera. Most importantly, sera from animals immunized with gp70 had a higher neutralizing activity when compared with the sera from animals immunized with p15E and sera from animals immunized with gp70 together with p15E had a higher neutralizing activity compared with sera from animals immunized with each antigen alone. These immunization studies are important for the development of vaccines against other retroviruses including the human immunodeficiency virus HIV-1.

【 授权许可】

   
2012 Denner et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Walker LM, Huber M, Doores KJ, Falkowska E, Pejchal R, Julien JP, Wang SK, Ramos A, Chan-Hui PY, Moyle M, Mitcham JL, Hammond PW, Olsen OA, Phung P, Fling S, Wong CH, Phogat S, Wrin T, Simek MD, Koff WC, Wilson IA, Burton DR, Poignard P, Protocol G Principal Investigators: Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 2011, 477:466-470.
• [2]Wu X, Yang ZY, Li Y, Hogerkorp CM, Schief WR, Seaman MS, Zhou T, Schmidt SD, Wu L, Xu L, Longo NS, McKee K, O'Dell S, Louder MK, Wycuff DL, Feng Y, Nason M, Doria-Rose N, Connors M, Kwong PD, Roederer M, Wyatt RT, Nabel GJ, Mascola JR: Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 2010, 329:856-861.
• [3]Montero M, van Houten NE, Wang X, Scott JK: The membrane-proximal external region of the human immunodeficiency virus type 1 envelope: dominant site of antibody neutralization and target for vaccine design. Microbiol Mol Biol Rev 2008, 72:54-84.
• [4]Fiebig U, Stephan O, Kurth R, Denner J: Neutralizing antibodies against conserved domains of p15E of porcine endogenous retroviruses: basis for a vaccine for xenotransplantation? Virology 2003, 307:406-413.
• [5]Langhammer S, Fiebig U, Kurth R, Denner J: Neutralising antibodies against the transmembrane protein of feline leukaemia virus (FeLV). Vaccine 2005, 23:3341-3348.
• [6]Langhammer S, Hubner J, Kurth R, Denner J: Antibodies neutralizing feline leukaemia virus (FeLV) in cats immunized with the transmembrane envelope protein p15E. Immunology 2006, 117:229-237.
• [7]Langhammer S, Fiebig U, Kurth R, Denner J: Increased neutralizing antibody response after simultaneous immunization with Leucogen and the feline leukemia virus transmembrane protein. Intervirology 2010, 54:78-86.
• [8]Langhammer S, Hübner J, Jarrett O, Kurth R, Denner J: Immunization with the transmembrane protein of a retrovirus, feline leukemia virus: absence of antigenemia following challenge. Antiviral Res 2011, 89:119-123.
• [9]Fiebig U, Hartmann MG, Bannert N, Kurth R, Denner J: Transspecies transmission of the endogenous koala retrovirus. J Virol 2006, 80:5651-5654.
• [10]Wilson CA: Porcine endogenous retroviruses and xenotransplantation. Cell Mol Life Sci 2008, 65:3399-3412.
• [11]Denner J, Tönjes RR: Infection barriers to succesful xenbotransplantation focusing on porcine endogenous retroviruses. Clin Microbiol Rev 2012, 25:318-343.
• [12]Kaulitz D, Fiebig U, Eschricht M, Wurzbacher C, Kurth R, Denner J: Generation of neutralising antibodies against porcine endogenous retroviruses (PERVs). Virology 2011, 411:78-86.
• [13]Fiebig U, Eschricht M, Schmolke M, Kurth R, Denner J: Mode of interaction between the HIV-1 neutralizing monoclonal antibody 2F5 and its epitope. AIDS 2009, 23:887-895.
• [14]Zwick MB, Labrijn AF, Wang M, Spenlehauer C, Saphire EO, Binley JM, Moore JP, Stiegler G, Katinger H, Burton DR, Parren PW: Broadly neutralizing antibodies targeted to the membrane-proximal external region of human immunodeficiency virus type 1 glycoprotein gp41. J Virol 2001, 75:10892-10905.
• [15]Muster T, Steindl F, Purtscher M, Trkola A, Klima A, Himmler G, Rüker F, Katinger H: A conserved neutralizing epitope on gp41 of human immunodeficiency virus type 1. J Virol 1993, 67:6642-6647.
• [16]Denner J: Towards an AIDS vaccine: the transmembrane envelope protein as target for broadly neutralizing antibodies. Hum Vaccin 2011, 7:4-9.
• [17]Behrendt R, Fiebig U, Kurth R, Denner J: Induction of antibodies binding to the membrane proximal external region (MPER) of gp36 of HIV-2. Intervirology 2012, 55:252-256.
• [18]Mühle M, Bleiholder A, Kolb S, Hübner J, Löchelt M, Denner J: Immunological properties of the transmembrane envelope protein of the feline foamy virus and its use for serological screening. Virology 2011, 412:333-340.
• [19]Bellamy-McIntyre AK, Lay CS, Baär S, Maerz AL, Talbo GH, Drummer HE, et al.: Functional links between the fusion peptide-proximal polar segment and membrane-proximal region of human immunodeficiency virus gp41 in distinct phases of membrane fusion. J Biol Chem 2007, 282:23104-23116.
• [20]Noah E, Biron Z, Naider F, Arshava B, Anglister J: The membrane proximal external region of the HIV-1 envelope glycoprotein gp41 contributes to the stabilization of the six-helix bundle formed with a matching N' peptide. Biochemistry 2008, 47:6782-6792.
• [21]Buzon V, Natrajan G, Schibli D, Campelo F, Kozlov MM, Weissenhorn W: Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions. PLoS Pathog 2010, 6:e1000880.
• [22]Lee SY, Howard TM, Rasheed S: Genetic analysis of the rat leukemia virus: influence of viral sequences in transduction of the c-ras proto-oncogene and expression of its transforming activity. J Virol 1998, 72:9906-9917.
• [23]De Lamarter JF, Monckton RP, Moroni C: Transcriptional control of endogenous virus genes in murine lymphocytes. J Gen Virol 1981, 52:371-375.
• [24]Stoye JP, Moroni C: Endogenous retrovirus expression in stimulated murine lymphocytes. Identification of a new locus controlling mitogen induction of a defective virus. J Exp Med 1983, 157:1660-1674.
• [25]Hirsch MS, Phillips SM, Solnik C, Black PH, Schwartz RS, Carpenter CB: Activation of leukemia viruses by graft-versus-host and mixed lymphocyte reactions in vitro. Proc Natl Acad Sci USA 1972, 69:1069-1072.
• [26]Denner J, Dorfman N: Small virus-like particles in leukosis-like syndrome induced by certain antigens and immunostimulators. Acta Biol Med German 1977, 36:1451-1458.
• [27]Nelson M, Nelson DS, Spradbrow PB, Kuchroo VK, Jennings PA, Cianciolo GJ, Snyderman R: Successful tumour immunotherapy: possible role of antibodies to anti-inflammatory factors produced by neoplasms. Clin Exp Immunol 1985, 61:109-117.
• [28]Büscher K, Hahn S, Hofmann M, Trefzer U, Ozel M, Sterry W, Löwer J, Löwer R, Kurth R, Denner J: Expression of the human endogenous retrovirus-K transmembrane envelope, Rec and Np9 proteins in melanomas and melanoma cell lines. Melanoma Res 2006, 16:223-234.
• [29]Ramsoondar J, Vaught T, Ball S, et al.: Production of transgenic pigs that express porcine endogenous retrovirus small interfering RNAs. Xenotransplantation 2009, 16:164-180.
• [30]Semaan M, Kaulitz D, Petersen B, Niemann H, Denner J: Long-term effects of PERV-specific RNA interference in transgenic pigs. Xenotransplantation 2012, 19:112-121.
• [31]Marciani DJ, Kensil CR, Beltz GA, Hung CH, Cronier J, Aubert A: Genetically-engineered subunit vaccine against feline leukaemia virus: protective immune response in cats. Vaccine 1991, 9:89-96.
• [32]Denner J, Specke V, Thiesen U, Karlas A, Kurth R: Genetic alterations of the long terminal repeat of an ecotropic porcine endogenous retrovirus during passage in human cells. Virology 2003, 314:125-133.
• [33]Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 2001, 25:402-408.