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Journal of Virology, May 2004, p. 5205-5215, Vol. 78, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.10.5205-5215.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The V1/V2 Domain of gp120 Is a Global Regulator of the Sensitivity of Primary Human Immunodeficiency Virus Type 1 Isolates to Neutralization by Antibodies Commonly Induced upon Infection

Abraham Pinter,1* William J. Honnen,1 Yuxian He,1 Miroslaw K. Gorny,2 Susan Zolla-Pazner,2,3 and Samuel C. Kayman1

Laboratory of Retroviral Biology, Public Health Research Institute, Newark, New Jersey 07103,1 Department of Pathology, New York University School of Medicine, New York, New York 10016,2 New York Veterans Affairs Medical Center, New York, New York 100103

Received 9 October 2003/ Accepted 15 January 2004

A major problem hampering the development of an effective vaccine against human immunodeficiency virus type 1 (HIV-1) is the resistance of many primary viral isolates to antibody-mediated neutralization. To identify factors responsible for this resistance, determinants of the large differences in neutralization sensitivities of HIV-1 pseudotyped with Env proteins derived from two prototypic clade B primary isolates were mapped. SF162 Env pseudotypes were neutralized very potently by a panel of sera from HIV-infected individuals, while JR-FL Env pseudotypes were neutralized by only a small fraction of these sera. This differential sensitivity to neutralization was also observed for a number of monoclonal antibodies (MAbs) directed against sites in the V2, V3, and CD4 binding domains, despite often similar binding affinities of these MAbs towards the two soluble rgp120s. The neutralization phenotypes were switched for chimeric Envs in which the V1/V2 domains of these two sequences were exchanged, indicating that the V1/V2 region regulated the overall neutralization sensitivity of these Envs. These results suggested that the inherent neutralization resistance of JR-FL, and presumably of related primary isolates, is to a great extent mediated by gp120 V1/V2 domain structure rather than by sequence variations at the target sites. Three MAbs (immunoglobulin G-b12, 2G12, and 2F5) previously reported to possess broad neutralizing activity for primary HIV-1 isolates neutralized JR-FL virus at least as well as SF162 virus and were not significantly affected by the V1/V2 domain exchanges. The rare antibodies capable of neutralizing a broad range of primary isolates thus appeared to be targeted to exceptional epitopes that are not sensitive to V1/V2 domain regulation of neutralization sensitivity.

* Corresponding author. Mailing address: Public Health Research Institute, 225 Warren St., Newark, NJ 07103-3535. Phone: (973) 854-3300. Fax: (973) 854-3301. E-mail: pinter{at}phri.org.

Journal of Virology, May 2004, p. 5205-5215, Vol. 78, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.10.5205-5215.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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