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Journal of Virology, June 2001, p. 5526-5540, Vol. 75, No. 12
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.12.5526-5540.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The Ability of an Oligomeric Human Immunodeficiency Virus Type 1 (HIV-1) Envelope Antigen To Elicit Neutralizing Antibodies against Primary HIV-1 Isolates Is Improved following Partial Deletion of the Second Hypervariable Region

S. W. Barnett,1 S. Lu,2 I. Srivastava,1 S. Cherpelis,3 A. Gettie,1,4 J. Blanchard,4 S. Wang,2 I. Mboudjeka,2 L. Leung,1 Y. Lian,1 A. Fong,1 C. Buckner,3 A. Ly,3 S. Hilt,1 J. Ulmer,1 C. T. Wild,5 J. R. Mascola,6,dagger and L. Stamatatos3,*

Chiron Corporation, Emeryville, California 94608-29161; University of Massachusetts Medical Center, Worcester, Massachusetts 016552; Aaron Diamond AIDS Research Center, The Rockfeller University, New York, New York 100163; Tulane Regional Primate Research Center, Covington, Louisiana 704334; Panacos Pharmaceuticals, Gaithersburg, Maryland 208775; and Walter Reed Army Institute of Research, Rockville, Maryland 208506

Received 6 February 2001/Accepted 20 March 2001

Partial deletion of the second hypervariable region from the envelope of the primary-like SF162 virus increases the exposure of certain neutralization epitopes and renders the virus, SF162Delta V2, highly susceptible to neutralization by clade B and non-clade B human immunodeficiency virus (HIV-positive) sera (L. Stamatatos and C. Cheng-Mayer, J. Virol. 78:7840-7845, 1998). This observation led us to propose that the modified, SF162Delta V2-derived envelope may elicit higher titers of cross-reactive neutralizing antibodies than the unmodified SF162-derived envelope. To test this hypothesis, we immunized rabbits and rhesus macaques with the gp140 form of these two envelopes. In rabbits, both immunogens elicited similar titers of binding antibodies but the modified immunogen was more effective in eliciting neutralizing antibodies, not only against the SF162Delta V2 and SF162 viruses but also against several heterologous primary HIV type 1 (HIV-1) isolates. In rhesus macaques both immunogens elicited potent binding antibodies, but again the modified immunogen was more effective in eliciting the generation of neutralizing antibodies against the SF162Delta V2 and SF162 viruses. Antibodies capable of neutralizing several, but not all, heterologous primary HIV-1 isolates tested were elicited only in macaques immunized with the modified immunogen. The efficiency of neutralization of these heterologous isolates was lower than that recorded against the SF162 isolate. Our results strongly suggest that although soluble oligomeric envelope subunit vaccines may elicit neutralizing antibody responses against heterologous primary HIV-1 isolates, these responses will not be broad and potent unless specific modifications are introduced to increase the exposure of conserved neutralization epitopes.

* Corresponding author. Mailing address: Aaron Diamond AIDS Research Center, 455 First Ave., 7th Floor, New York, NY 10016. Phone: (212) 448-5000. Fax: (212) 725-1126. E-mail: lstamata{at}adarc.org.

dagger Present address: Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892.

Journal of Virology, June 2001, p. 5526-5540, Vol. 75, No. 12
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.12.5526-5540.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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