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

doi:10.1128/JVI.75.12.5526-5540.2001

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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^, 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 exposureof certain neutralization epitopes and renders the virus, SF162 $Delta$ V2,highly susceptible to neutralization by clade B and non-cladeB human immunodeficiency virus (HIV-positive) sera (L. Stamatatosand C. Cheng-Mayer, J. Virol. 78:7840-7845, 1998). This observationled us to propose that the modified, SF162 $Delta$ V2-derived envelopemay elicit higher titers of cross-reactive neutralizing antibodiesthan the unmodified SF162-derived envelope. To test this hypothesis,we immunized rabbits and rhesus macaques with the gp140 form ofthese two envelopes. In rabbits, both immunogens elicited similartiters of binding antibodies but the modified immunogen was moreeffective in eliciting neutralizing antibodies, not only againstthe SF162 $Delta$ V2 and SF162 viruses but also against several heterologousprimary HIV type 1 (HIV-1) isolates. In rhesus macaques both immunogenselicited potent binding antibodies, but again the modified immunogenwas more effective in eliciting the generation of neutralizingantibodies against the SF162 $Delta$ V2 and SF162 viruses. Antibodiescapable of neutralizing several, but not all, heterologous primaryHIV-1 isolates tested were elicited only in macaques immunizedwith the modified immunogen. The efficiency of neutralizationof these heterologous isolates was lower than that recorded againstthe SF162 isolate. Our results strongly suggest that althoughsoluble oligomeric envelope subunit vaccines may elicit neutralizingantibody responses against heterologous primary HIV-1 isolates,these responses will not be broad and potent unless specific modificationsare introduced to increase the exposure of conserved neutralizationepitopes.

^* 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.

Present address: Vaccine Research Center, National Institutes of Health, Bethesda, MD20892.

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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