This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mortara, L.
Right arrow Articles by Bourgault-Villada, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mortara, L.
Right arrow Articles by Bourgault-Villada, I.

 Previous Article  |  Next Article 

J Virol, February 1998, p. 1403-1410, Vol. 72, No. 2
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Selection of Virus Variants and Emergence of Virus Escape Mutants after Immunization with an Epitope Vaccine

Lorenzo Mortara,1,* Franck Letourneur,2 Helene Gras-masse,3 Alain Venet,1 Jean-Gerard Guillet,1 and Isabelle Bourgault-Villada1

Laboratoire d'Immunologie des Pathologies Infectieuses et Tumorales, INSERM U445,1 and Unité de Séquençage UFR 18,2 Institut Cochin de Génétique Moléculaire, Université René Descartes, Hôpital Cochin, 75014 Paris, and Laboratoire de Chimie des Biomolécules, Université de Lille II, Institut Pasteur de Lille, 59019 Lille Cedex,3 France

Received 17 June 1997/Accepted 4 November 1997

In this report, we assessed the evolution of the cytotoxic T-lymphocyte (CTL) response induced by an epitope vaccine. In two macaques immunized with a mixture of lipopeptides derived from simian immunodeficiency virus (SIV) Nef and Gag proteins, CTL responses were directed against the same, single epitope of the Nef protein (amino acids 128 to 137) presenting an alanine at position 136 (Nef 128-137/136A). However, after 5 months of SIV infection, peripheral blood mononuclear cells from both macaques lost their ability to be stimulated by autologous SIV-infected cells while still retaining their capacity to generate cytotoxic responses after specific Nef 128-137/136A peptide stimulation. The sequences of the pathogenic viral isolate used for the challenge showed a mixture of several variants. Within the Nef epitopic sequence from amino acids 128 to 137, 82% of viral variants expressed the epitopic peptide Nef 128-137/136A; the remaining variants presented a threonine at position 136 (Nef 128-137/136T). In contrast, sequence analysis of cloned proviral DNA obtained from both macaques 5 months after SIV challenge showed a different pattern of quasi-species variants; 100% of clones presented a threonine at position 136 (Nef 128-137/136T), suggesting the disappearance of viral variants with an alanine at this position under antiviral pressure exerted by Nef 128-137/136A-specific CTLs. In addition, 12 months after SIV challenge, six of eight clones from one macaque presented a glutamic acid at position 131 (Nef 128-137/131E+136T), which was not found in the infecting isolate. Furthermore, CTLs generated very early after SIV challenge were able to lyse cells sensitized with the Nef 128-137/136A epitope. In contrast, lysis was significantly less effective or even did not occur when either the selected peptide Nef 128-137/136T or the escape variant peptide Nef 128-137/131E+136T was used in a target cell sensitization assay. Dose analysis of peptides used to sensitize target cells as well as a major histocompatibility complex (MHC)-peptide stability assay suggested that the selected peptide Nef 128-137/136T has an altered capacity to bind to the MHC. These data suggest that CTL pressure leads to the selection of viral variants and to the emergence of escape mutants and supports the fact that immunization should elicit broad CTL responses.

* Corresponding author. Mailing address: ICGM, INSERM U445, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France. Phone: (33) 1 44 07 18 21. Fax: (33) 1 44 07 14 25. E-mail: mortara{at}icgm.cochin.inserm.fr.




This article has been cited by other articles:

  • Sadagopal, S., Amara, R. R., Kannanganat, S., Sharma, S., Chennareddi, L., Robinson, H. L. (2008). Expansion and Exhaustion of T-Cell Responses during Mutational Escape from Long-Term Viral Control in Two DNA/Modified Vaccinia Virus Ankara-Vaccinated and Simian-Human Immunodeficiency Virus SHIV-89.6P-Challenged Macaques. J. Virol. 82: 4149-4153 [Abstract] [Full Text]  
  • Asquith, B., McLean, A. R. (2007). In vivo CD8+ T cell control of immunodeficiency virus infection in humans and macaques. Proc. Natl. Acad. Sci. USA 104: 6365-6370 [Abstract] [Full Text]  
  • Turnbull, E. L., Lopes, A. R., Jones, N. A., Cornforth, D., Newton, P., Aldam, D., Pellegrino, P., Turner, J., Williams, I., Wilson, C. M., Goepfert, P. A., Maini, M. K., Borrow, P. (2006). HIV-1 Epitope-Specific CD8+ T Cell Responses Strongly Associated with Delayed Disease Progression Cross-Recognize Epitope Variants Efficiently. J. Immunol. 176: 6130-6146 [Abstract] [Full Text]  
  • Mehandru, S., Wrin, T., Galovich, J., Stiegler, G., Vcelar, B., Hurley, A., Hogan, C., Vasan, S., Katinger, H., Petropoulos, C. J., Markowitz, M. (2004). Neutralization Profiles of Newly Transmitted Human Immunodeficiency Virus Type 1 by Monoclonal Antibodies 2G12, 2F5, and 4E10. J. Virol. 78: 14039-14042 [Abstract] [Full Text]  
  • Jones, N. A., Wei, X., Flower, D. R., Wong, M., Michor, F., Saag, M. S., Hahn, B. H., Nowak, M. A., Shaw, G. M., Borrow, P. (2004). Determinants of Human Immunodeficiency Virus Type 1 Escape from the Primary CD8+ Cytotoxic T Lymphocyte Response. JEM 200: 1243-1256 [Abstract] [Full Text]  
  • Bartholdy, C., Stryhn, A., Christensen, J. P., Thomsen, A. R. (2004). Single-Epitope DNA Vaccination Prevents Exhaustion and Facilitates a Broad Antiviral CD8+ T Cell Response during Chronic Viral Infection. J. Immunol. 173: 6284-6293 [Abstract] [Full Text]  
  • Loffredo, J. T., Sidney, J., Wojewoda, C., Dodds, E., Reynolds, M. R., Napoe, G., Mothe, B. R., O'Connor, D. H., Wilson, N. A., Watkins, D. I., Sette, A. (2004). Identification of Seventeen New Simian Immunodeficiency Virus-Derived CD8+ T Cell Epitopes Restricted by the High Frequency Molecule, Mamu-A*02, and Potential Escape from CTL Recognition. J. Immunol. 173: 5064-5076 [Abstract] [Full Text]  
  • Friedrich, T. C., McDermott, A. B., Reynolds, M. R., Piaskowski, S., Fuenger, S., de Souza, I. P., Rudersdorf, R., Cullen, C., Yant, L. J., Vojnov, L., Stephany, J., Martin, S., O'Connor, D. H., Wilson, N., Watkins, D. I. (2004). Consequences of Cytotoxic T-Lymphocyte Escape: Common Escape Mutations in Simian Immunodeficiency Virus Are Poorly Recognized in Naive Hosts. J. Virol. 78: 10064-10073 [Abstract] [Full Text]  
  • Friedrich, T. C., Frye, C. A., Yant, L. J., O'Connor, D. H., Kriewaldt, N. A., Benson, M., Vojnov, L., Dodds, E. J., Cullen, C., Rudersdorf, R., Hughes, A. L., Wilson, N., Watkins, D. I. (2004). Extraepitopic Compensatory Substitutions Partially Restore Fitness to Simian Immunodeficiency Virus Variants That Escape from an Immunodominant Cytotoxic-T-Lymphocyte Response. J. Virol. 78: 2581-2585 [Abstract] [Full Text]  
  • Peyerl, F. W., Barouch, D. H., Yeh, W. W., Bazick, H. S., Kunstman, J., Kunstman, K. J., Wolinsky, S. M., Letvin, N. L. (2003). Simian-Human Immunodeficiency Virus Escape from Cytotoxic T-Lymphocyte Recognition at a Structurally Constrained Epitope. J. Virol. 77: 12572-12578 [Abstract] [Full Text]  
  • Kong, W.-P., Huang, Y., Yang, Z.-Y., Chakrabarti, B. K., Moodie, Z., Nabel, G. J. (2003). Immunogenicity of Multiple Gene and Clade Human Immunodeficiency Virus Type 1 DNA Vaccines. J. Virol. 77: 12764-12772 [Abstract] [Full Text]  
  • Smith, S. M., Pentlicky, S., Klase, Z., Singh, M., Neuveut, C., Lu, C.-y., Reitz, M. S. Jr., Yarchoan, R., Marx, P. A., Jeang, K.-T. (2003). An in Vivo Replication-important Function in the Second Coding Exon of Tat Is Constrained against Mutation despite Cytotoxic T Lymphocyte Selection. J. Biol. Chem. 278: 44816-44825 [Abstract] [Full Text]  
  • Gahery-Segard, H., Pialoux, G., Figueiredo, S., Igea, C., Surenaud, M., Gaston, J., Gras-Masse, H., Levy, J.-P., Guillet, J.-G. (2003). Long-Term Specific Immune Responses Induced in Humans by a Human Immunodeficiency Virus Type 1 Lipopeptide Vaccine: Characterization of CD8+-T-Cell Epitopes Recognized. J. Virol. 77: 11220-11231 [Abstract] [Full Text]  
  • Haicheur, N., Benchetrit, F., Amessou, M., Leclerc, C., Falguieres, T., Fayolle, C., Bismuth, E., Fridman, W. H., Johannes, L., Tartour, E. (2003). The B subunit of Shiga toxin coupled to full-size antigenic protein elicits humoral and cell-mediated immune responses associated with a Th1-dominant polarization. Int Immunol 15: 1161-1171 [Abstract] [Full Text]  
  • Novitsky, V., Gilbert, P., Peter, T., McLane, M. F., Gaolekwe, S., Rybak, N., Thior, I., Ndung'u, T., Marlink, R., Lee, T. H., Essex, M. (2002). Association between Virus-Specific T-Cell Responses and Plasma Viral Load in Human Immunodeficiency Virus Type 1 Subtype C Infection. J. Virol. 77: 882-890 [Abstract] [Full Text]  
  • Vogel, T. U., Horton, H., Fuller, D. H., Carter, D. K., Vielhuber, K., O'Connor, D. H., Shipley, T., Fuller, J., Sutter, G., Erfle, V., Wilson, N., Picker, L. J., Watkins, D. I. (2002). Differences Between T Cell Epitopes Recognized After Immunization and After Infection. J. Immunol. 169: 4511-4521 [Abstract] [Full Text]  
  • McMichael, A., Mwau, M., Hanke, T. (2002). Design and tests of an HIV vaccine. Br Med Bull 62: 87-98 [Abstract] [Full Text]  
  • Horton, H., Vogel, T. U., Carter, D. K., Vielhuber, K., Fuller, D. H., Shipley, T., Fuller, J. T., Kunstman, K. J., Sutter, G., Montefiori, D. C., Erfle, V., Desrosiers, R. C., Wilson, N., Picker, L. J., Wolinsky, S. M., Wang, C., Allison, D. B., Watkins, D. I. (2002). Immunization of Rhesus Macaques with a DNA Prime/Modified Vaccinia Virus Ankara Boost Regimen Induces Broad Simian Immunodeficiency Virus (SIV)-Specific T-Cell Responses and Reduces Initial Viral Replication but Does Not Prevent Disease Progression following Challenge with Pathogenic SIVmac239. J. Virol. 76: 7187-7202 [Abstract] [Full Text]  
  • Allen, T. M., Mothé, B. R., Sidney, J., Jing, P., Dzuris, J. L., Liebl, M. E., Vogel, T. U., O'Connor, D. H., Wang, X., Wussow, M. C., Thomson, J. A., Altman, J. D., Watkins, D. I., Sette, A. (2001). CD8+ Lymphocytes from Simian Immunodeficiency Virus-Infected Rhesus Macaques Recognize 14 Different Epitopes Bound by the Major Histocompatibility Complex Class I Molecule Mamu-A*01: Implications for Vaccine Design and Testing. J. Virol. 75: 738-749 [Abstract] [Full Text]  
  • Chen, Z. W., Craiu, A., Shen, L., Kuroda, M. J., Iroku, U. C., Watkins, D. I., Voss, G., Letvin, N. L. (2000). Simian Immunodeficiency Virus Evades a Dominant Epitope-Specific Cytotoxic T Lymphocyte Response Through a Mutation Resulting in the Accelerated Dissociation of Viral Peptide and MHC Class I. J. Immunol. 164: 6474-6479 [Abstract] [Full Text]  
  • Price, G. E., Ou, R., Jiang, H., Huang, L., Moskophidis, D. (2000). Viral Escape by Selection of Cytotoxic T Cell-Resistant Variants in Influenza a Virus Pneumonia. JEM 191: 1853-1868 [Abstract] [Full Text]  
  • Gahéry-Ségard, H., Pialoux, G., Charmeteau, B., Sermet, S., Poncelet, H., Raux, M., Tartar, A., Lévy, J.-P., Gras-Masse, H., Guillet, J.-G. (2000). Multiepitopic B- and T-Cell Responses Induced in Humans by a Human Immunodeficiency Virus Type 1 Lipopeptide Vaccine. J. Virol. 74: 1694-1703 [Abstract] [Full Text]  
  • Loing, E., Andrieu, M., Thiam, K., Schorner, D., Wiesmuller, K.-H., Hosmalin, A., Jung, G., Gras-Masse, H. (2000). Extension of HLA-A*0201-Restricted Minimal Epitope by N{epsilon}-Palmitoyl-lysine Increases the Life Span of Functional Presentation to Cytotoxic T Cells. J. Immunol. 164: 900-907 [Abstract] [Full Text]  
  • Woodberry, T., Gardner, J., Mateo, L., Eisen, D., Medveczky, J., Ramshaw, I. A., Thomson, S. A., Ffrench, R. A., Elliott, S. L., Firat, H., Lemonnier, F. A., Suhrbier, A. (1999). Immunogenicity of a Human Immunodeficiency Virus (HIV) Polytope Vaccine Containing Multiple HLA A2 HIV CD8+ Cytotoxic T-Cell Epitopes. J. Virol. 73: 5320-5325 [Abstract] [Full Text]  
  • Mortara, L., Gras-Masse, H., Rommens, C., Venet, A., Guillet, J.-G., Bourgault-Villada, I. (1999). Type 1 CD4+ T-Cell Help Is Required for Induction of Antipeptide Multispecific Cytotoxic T Lymphocytes by a Lipopeptidic Vaccine in Rhesus Macaques. J. Virol. 73: 4447-4451 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»