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Journal of Virology, January 2008, p. 949-956, Vol. 82, No. 2
0022-538X/08/$08.00+0     doi:10.1128/JVI.02143-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The First Hypervariable Region of the gp120 Env Glycoprotein Defines the Neutralizing Susceptibility of Heterologous Human Immunodeficiency Virus Type 1 Isolates to Neutralizing Antibodies Elicited by the SF162gp140 Immunogen

Lance K. Ching,^1,2, Giorgos Vlachogiannis,^1,3, Katherine A. Bosch,^1,2 and Leonidas Stamatatos^1,2*

Seattle Biomedical Research Institute, Seattle, Washington 98109,¹ Department of Pathobiology, University of Washington, Seattle, Washington 98109,² Department of Molecular Biology & Genetics, Democritus University of Thrace, Alexandrou polis, Greece³

Received 28 September 2007/ Accepted 31 October 2007

Current vaccine efforts to elicit cross-reactive neutralizing antibodies (NAbs) against human immunodeficiency virus (HIV) focus on the engineering of soluble mimetics of the trimeric HIV Env glycoprotein (commonly termed gp140 immunogens). Such immunogens are thought to be more effective than previously tested monomeric gp120 immunogens at eliciting cross-reactive NAbs. Still, the breadth of neutralizing antibody responses elicited by gp140 immunogens is narrow. Understanding why antibodies elicited by gp140 immunogens fail to neutralize a wide range of heterologous primary HIV isolates is necessary for improving the design of such immunogens. We previously reported that antibodies elicited in macaques by SF162 Env-derived gp140 immunogens fail to neutralize several heterologous "neutralization-resistant" primary HIV type 1 isolates, such as JRFL, ADA, and YU2. Here we show that by replacing the V1 region of Env on these heterologous viruses with that of SF162, we render them highly susceptible to neutralization by the SF162gp140-elicited antibodies. We observed that viral neutralization was mediated not only by vaccine-elicited anti-V1 but also by anti-V3 antibodies and antibodies directed against as yet unidentified Env regions, depending on the heterologous Env background. Our study indicates that common neutralization epitopes are differentially exposed on diverse primary HIV isolates and that the V1 loop contributes to this differential exposure. Therefore, the antibody responses elicited by soluble gp140 immunogens will have to overcome several distinct obstacles in order to neutralize diverse primary HIV isolates.

Published ahead of print on 14 November 2007.

Contributed equally.

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