This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by López-Bueno, A. Articles by Almendral, J. M. Search for Related Content PubMed PubMed Citation Articles by López-Bueno, A. Articles by Almendral, J. M.

 Previous Article  |  Next Article 

Journal of Virology, February 2003, p. 2701-2708, Vol. 77, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.4.2701-2708.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

High Mutant Frequency in Populations of a DNA Virus Allows Evasion from Antibody Therapy in an Immunodeficient Host

Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), 28049 Cantoblanco, Madrid, Spain

Received 16 September 2002/ Accepted 13 November 2002

The degree of genetic heterogeneity of DNA virus populations in nature and its consequences for disease control are virtually unknown. The parvovirus minute virus of mice (MVMi) was used here to investigate (i) the frequency of antibody-escape mutants in populations of a DNA virus and (ii) the ability of a DNA virus to evade in the long-term a passive monoclonal antibody (MAb) therapy in an immunodeficient natural host. Independent clonal populations of MVMi harbored a high proportion of mutants resistant to neutralizing MAb (mutant frequency = [2.8 ± 0.5] x 10^-5) that rapidly evolved under antibody pressure in culture to become mixtures dominated by genotypically diverse escape mutants. Immunodeficient mice naturally infected with clonal populations of MVMi and subsequently treated by intravenous injections of MAb were initially protected from the characteristic viral induced lethal leukopenia. However, some treated animals developed a delayed severe leukopenic syndrome associated with the emergence of genetically heterogeneous populations of MAb-resistant mutants in the MVMi main target organs. The 11 plaque-purified viruses analyzed from an antibody-resistant population obtained from one animal corresponded to four different mutant genotypes, although their consensus sequence remained wild type. All cloned escape mutants harbored single radical amino acid changes within a stretch of seven residues in a surface-exposed loop at the threefold axes of the capsid. This antigenic site, which can tolerate radical changes preserving MVMi pathogenic potential, may thereby allow the virus to evade the immune control. These findings indicate a high genetic heterogeneity and rapid adaptation of populations of a mammal DNA virus in vivo and provide a genetic basis for the failure of passive immunotherapy in the natural host.

This article has been cited by other articles:

• Martin, V., Domingo, E. (2008). Influence of the Mutant Spectrum in Viral Evolution: Focused Selection of Antigenic Variants in a Reconstructed Viral Quasispecies. Mol Biol Evol 25: 1544-1554 [Abstract] [Full Text]  
• Engelsma, D., Valle, N., Fish, A., Salome, N., Almendral, J. M., Fornerod, M. (2008). A Supraphysiological Nuclear Export Signal Is Required for Parvovirus Nuclear Export. Mol. Biol. Cell 19: 2544-2552 [Abstract] [Full Text]  
• Lopez-Bueno, A., Segovia, J. C., Bueren, J. A., O'Sullivan, M. G., Wang, F., Tattersall, P., Almendral, J. M. (2008). Evolution to Pathogenicity of the Parvovirus Minute Virus of Mice in Immunodeficient Mice Involves Genetic Heterogeneity at the Capsid Domain That Determines Tropism. J. Virol. 82: 1195-1203 [Abstract] [Full Text]  
• Schneider, B., Hone, A., Tolba, R. H., Fischer, H.-P., Blumel, J., Eis-Hubinger, A. M. (2008). Simultaneous persistence of multiple genome variants of human parvovirus B19. J. Gen. Virol. 89: 164-176 [Abstract] [Full Text]  
• Arguello-Astorga, G., Ascencio-Ibanez, J. T., Dallas, M. B., Orozco, B. M., Hanley-Bowdoin, L. (2007). High-Frequency Reversion of Geminivirus Replication Protein Mutants during Infection. J. Virol. 81: 11005-11015 [Abstract] [Full Text]  
• Kaufmann, B., Lopez-Bueno, A., Mateu, M. G., Chipman, P. R., Nelson, C. D. S., Parrish, C. R., Almendral, J. M., Rossmann, M. G. (2007). Minute Virus of Mice, a Parvovirus, in Complex with the Fab Fragment of a Neutralizing Monoclonal Antibody. J. Virol. 81: 9851-9858 [Abstract] [Full Text]  
• Zhao, X., Liu, E., Chen, F.-P., Sullender, W. M. (2006). In Vitro and In Vivo Fitness of Respiratory Syncytial Virus Monoclonal Antibody Escape Mutants. J. Virol. 80: 11651-11657 [Abstract] [Full Text]  
• Norja, P., Hokynar, K., Aaltonen, L.-M., Chen, R., Ranki, A., Partio, E. K., Kiviluoto, O., Davidkin, I., Leivo, T., Eis-Hubinger, A. M., Schneider, B., Fischer, H.-P., Tolba, R., Vapalahti, O., Vaheri, A., Soderlund-Venermo, M., Hedman, K. (2006). Bioportfolio: Lifelong persistence of variant and prototypic erythrovirus DNA genomes in human tissue. Proc. Natl. Acad. Sci. USA 103: 7450-7453 [Abstract] [Full Text]  
• Lopez-Bueno, A., Rubio, M.-P., Bryant, N., McKenna, R., Agbandje-McKenna, M., Almendral, J. M. (2006). Host-Selected Amino Acid Changes at the Sialic Acid Binding Pocket of the Parvovirus Capsid Modulate Cell Binding Affinity and Determine Virulence. J. Virol. 80: 1563-1573 [Abstract] [Full Text]  
• Mani, B., Baltzer, C., Valle, N., Almendral, J. M., Kempf, C., Ros, C. (2006). Low pH-Dependent Endosomal Processing of the Incoming Parvovirus Minute Virus of Mice Virion Leads to Externalization of the VP1 N-Terminal Sequence (N-VP1), N-VP2 Cleavage, and Uncoating of the Full-Length Genome. J. Virol. 80: 1015-1024 [Abstract] [Full Text]  
• Rubio, M.-P., Lopez-Bueno, A., Almendral, J. M. (2005). Virulent Variants Emerging in Mice Infected with the Apathogenic Prototype Strain of the Parvovirus Minute Virus of Mice Exhibit a Capsid with Low Avidity for a Primary Receptor. J. Virol. 79: 11280-11290 [Abstract] [Full Text]  
• Reguera, J., Grueso, E., Carreira, A., Sanchez-Martinez, C., Almendral, J. M., Mateu, M. G. (2005). Functional Relevance of Amino Acid Residues Involved in Interactions with Ordered Nucleic Acid in a Spherical Virus. J. Biol. Chem. 280: 17969-17977 [Abstract] [Full Text]  
• Zhao, X., Sullender, W. M. (2005). In Vivo Selection of Respiratory Syncytial Viruses Resistant to Palivizumab. J. Virol. 79: 3962-3968 [Abstract] [Full Text]  
• Lopez-Bueno, A., Valle, N., Gallego, J. M., Perez, J., Almendral, J. M. (2004). Enhanced Cytoplasmic Sequestration of the Nuclear Export Receptor CRM1 by NS2 Mutations Developed in the Host Regulates Parvovirus Fitness. J. Virol. 78: 10674-10684 [Abstract] [Full Text]  
• Maroto, B., Valle, N., Saffrich, R., Almendral, J. M. (2004). Nuclear Export of the Nonenveloped Parvovirus Virion Is Directed by an Unordered Protein Signal Exposed on the Capsid Surface. J. Virol. 78: 10685-10694 [Abstract] [Full Text]  
• Reguera, J., Carreira, A., Riolobos, L., Almendral, J. M., Mateu, M. G. (2004). Role of interfacial amino acid residues in assembly, stability, and conformation of a spherical virus capsid. Proc. Natl. Acad. Sci. USA 101: 2724-2729 [Abstract] [Full Text]  
• Carreira, A., Menendez, M., Reguera, J., Almendral, J. M., Mateu, M. G. (2004). In Vitro Disassembly of a Parvovirus Capsid and Effect on Capsid Stability of Heterologous Peptide Insertions in Surface Loops. J. Biol. Chem. 279: 6517-6525 [Abstract] [Full Text]  
• Segovia, J. C., Guenechea, G., Gallego, J. M., Almendral, J. M., Bueren, J. A. (2003). Parvovirus Infection Suppresses Long-Term Repopulating Hematopoietic Stem Cells. J. Virol. 77: 8495-8503 [Abstract] [Full Text]