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Journal of Virology, June 2005, p. 6909-6917, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.6909-6917.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The C108g Epitope in the V2 Domain of gp120 Functions as a Potent Neutralization Target When Introduced into Envelope Proteins Derived from Human Immunodeficiency Virus Type 1 Primary Isolates

Abraham Pinter,1* William J. Honnen,1 Paul D'Agostino,1 Miroslaw K. Gorny,2 Susan Zolla-Pazner,2,3 and Samuel C. Kayman1,{dagger}

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 22 October 2004/ Accepted 20 January 2005

Monoclonal antibodies (MAbs) directed against epitopes in the V2 domain of human immunodeficiency virus type 1 gp120 often possess neutralizing activity, but these generally are highly type specific, neutralize only laboratory isolates, or have low potency. The most potent of these is C108g, directed against a type-specific epitope in HXB2 and BaL gp120s, which is glycan dependent and, in contrast to previous reports, dependent on intact disulfide bonds. This epitope was introduced into two primary Envs, derived from a neutralization-sensitive (SF162) and a neutralization-resistant (JR-FL) isolate, by substitution of two residues and, for SF162, addition of an N-linked glycosylation site. C108g effectively neutralized both variant Envs with considerably higher potency than standard MAbs against the V3 and CD4-binding domains and the broadly neutralizing MAbs 2G12 and 2F5. These amino acid substitutions also introduced the epitope recognized by a second V2-specific MAb, 10/76b, but this MAb possessed potent neutralizing activity only in the absence of the glycan required for C108g reactivity. In contrast to other gp120-specific neutralizing MAbs, C108g did not block binding of soluble Env proteins to either the CD4 or the CCR5 receptor, but studies with a fusion-arrested Env indicated that C108g neutralized at a step preceding the one blocked by the gp41-specific MAb, 2F5. These results indicate that the V1/V2 domain possesses targets that mediate potent neutralization of primary viral isolates via a novel mechanism and suggest that inclusion of carbohydrate determinants into these epitopes may help overcome the indirect masking effects that limit the neutralizing potency of antibodies commonly produced after infection.

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

{dagger} Deceased.

Journal of Virology, June 2005, p. 6909-6917, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.6909-6917.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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