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Journal of Virology, October 2008, p. 9739-9752, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00871-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Potent Antibody-Mediated Neutralization and Evolution of Antigenic Escape Variants of Simian Immunodeficiency Virus Strain SIVmac239 In Vivo{triangledown}

Shuji Sato,1,{dagger} Eloisa Yuste,1 William A. Lauer,1 Eun Hyuk Chang,1 Jennifer S. Morgan,1 Jacqueline G. Bixby,1 Jeffrey D. Lifson,2 Ronald C. Desrosiers,1 and Welkin E. Johnson1*

New England Primate Research Center, Department of Microbiology and Molecular Genetics, Harvard Medical School, Southborough, Massachusetts 01772,1 AIDS and Cancer Virus Program, SAIC Frederick, Inc., National Cancer Institute, Frederick, Maryland 217022

Received 24 April 2008/ Accepted 21 July 2008

Here, we describe the evolution of antigenic escape variants in a rhesus macaque that developed unusually high neutralizing antibody titers to SIVmac239. By 42 weeks postinfection, 50% neutralization of SIVmac239 was achieved with plasma dilutions of 1:1,000. Testing of purified immunoglobulin confirmed that the neutralizing activity was antibody mediated. Despite the potency of the neutralizing antibody response, the animal displayed a typical viral load profile and progressed to terminal AIDS with a normal time course. Viral envelope sequences from week 16 and week 42 plasma contained an excess of nonsynonymous substitutions, predominantly in V1 and V4, including individual sites with ratios of nonsynonymous to synonymous substitution rates (dN/dS) highly suggestive of strong positive selection. Recombinant viruses encoding envelope sequences isolated from these time points remained resistant to neutralization by all longitudinal plasma samples, revealing the failure of the animal to mount secondary responses to the escaped variants. Substitutions at two sites with significant dN/dS values, one in V1 and one in V4, were independently sufficient to confer nearly complete resistance to neutralization. Substitutions at three additional sites, one in V4 and two in gp41, conferred moderate to high levels of resistance when tested individually. All the amino acid changes leading to escape resulted from single nucleotide substitutions. The observation that antigenic escape resulted from individual, single amino acid replacements at sites well separated in current structural models of Env indicates that the virus can utilize multiple independent pathways to rapidly achieve similar levels of resistance.

* Corresponding author. Mailing address: New England Primate Research Center, Department of Microbiology and Molecular Genetics, Harvard Medical School, Southborough, MA 01772. Phone: (508) 624-8041. Fax: (508) 786-3317. E-mail: welkin_johnson{at}hms.harvard.edu

{triangledown} Published ahead of print on 30 July 2008.

{dagger} Present address: Cell Signaling Technology, Danvers, MA 01923.

Journal of Virology, October 2008, p. 9739-9752, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00871-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Peut, V., Campbell, S., Gaeguta, A., Center, R. J., Wilson, K., Alcantara, S., Fernandez, C. S., Purcell, D. F. J., Kent, S. J. (2009). Balancing Reversion of Cytotoxic T-Lymphocyte and Neutralizing Antibody Escape Mutations within Human Immunodeficiency Virus Type 1 Env upon Transmission. J. Virol. 83: 8986-8992 [Abstract] [Full Text]  
  • Yuste, E., Bixby, J., Lifson, J., Sato, S., Johnson, W., Desrosiers, R. (2008). Glycosylation of gp41 of Simian Immunodeficiency Virus Shields Epitopes That Can Be Targets for Neutralizing Antibodies. J. Virol. 82: 12472-12486 [Abstract] [Full Text]  


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