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Journal of Virology, September 2003, p. 9993-10003, Vol. 77, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.18.9993-10003.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Assorted Mutations in the Envelope Gene of Simian Immunodeficiency Virus Lead to Loss of Neutralization Resistance against Antibodies Representing a Broad Spectrum of Specificities

Welkin E. Johnson,1 Hannah Sanford,1 Linda Schwall,1 Dennis R. Burton,2 Paul W. H. I. Parren,2,3 James E. Robinson,4 and Ronald C. Desrosiers1*

New England Regional Primate Research Center, Department of Microbiology and Molecular Genetics, Harvard Medical School, Southborough, Massachusetts 01772-9102,1 Departments of Immunology and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037,3 Department of Pediatrics, Tulane University Medical School, New Orleans Louisiana 70112,4 Genmab, 3584 CK Utrecht, The Netherlands2

Received 15 April 2003/ Accepted 28 June 2003

Simian immunodeficiency virus (SIV) of macaques isolate SIVmac239 is highly resistant to neutralization by polyclonal antisera or monoclonal antibodies, a property that it shares with most primary isolates of human immunodeficiency virus type 1 (HIV-1). This resistance is important for the ability of the virus to persist at high levels in vivo. To explore the physical features of the viral envelope complex that contribute to the neutralization-resistant phenotype, we examined a panel of SIVmac239 derivatives for sensitivity to neutralization by a large collection of monoclonal antibodies (MAbs). These MAbs recognize both linear and conformational epitopes throughout the viral envelope proteins. The variant viruses included three derivatives of SIVmac239 with substitutions in specific N-linked glycosylation sites of gp120 and a fourth variant that lacked the100 amino acids that encompass the V1 and V2 loops. Also included in this study was SIVmac316, a variant of SIVmac239 with distributed mutations in env that confer significantly increased replicative capacity in tissue macrophages. These viruses were chosen to represent a broad range of neutralization sensitivities based on susceptibility to pooled, SIV-positive plasma. All three of these very different kinds of mutations (amino acid substitutions, elimination of N-glycan attachment sites, and a 100-amino-acid deletion spanning variable loops V1 and V2) dramatically increased sensitivity to neutralization by MAbs from multiple competition groups. Thus, the mutations did not simply expose localized epitopes but rather conferred global increases in neutralization sensitivity. The removal of specific N-glycan attachment sites from V1 and V2 led to increased sensitivity to neutralization by antibodies recognizing epitopes from both within and outside of the V1-V2 sequence. Surprisingly, while most of the mutations that gave rise to increased sensitivity were located in the N-terminal half of gp120 (surface subunit [SU]), the greatest increases in sensitivity were to MAbs recognizing the C-terminal half of gp120 or the ectodomain of gp41 (transmembrane subunit [TM]). This reagent set and information should now be useful for defining the physical, structural, thermodynamic, and kinetic factors that influence relative sensitivity to antibody-mediated neutralization.

* Corresponding author. Mailing address: New England Regional Primate Research Center, One Pine Hill Dr., Box 9102, Southborough, MA 01772-9102. Phone: (508) 624-8002. Fax: (508) 624-8190. E-mail: ronald_desrosiers{at}hms.harvard.edu.

Journal of Virology, September 2003, p. 9993-10003, Vol. 77, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.18.9993-10003.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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