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Journal of Virology, July 2006, p. 7127-7135, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.02619-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Factors Determining the Breadth and Potency of Neutralization by V3-Specific Human Monoclonal Antibodies Derived from Subjects Infected with Clade A or Clade B Strains of Human Immunodeficiency Virus Type 1

Public Health Research Institute, Newark, New Jersey,¹ NYU School of Medicine, New York, New York,² New York Veterans Affairs Medical Center, New York, New York,³ Department of Medicine, New Jersey Medical School, UMDNJ, Newark, New Jersey⁴

Received 15 December 2005/ Accepted 26 April 2006

The neutralizing activities of anti-V3 antibodies for HIV-1 isolates is affected both by sequence variation within V3 and by epitope masking by the V1/V2 domain. To analyze the relative contribution of V3 sequence variation, chimeric Env genes that contained consensus V3 sequences from seven HIV-1 subtypes in the neutralization-sensitive SF162 Env backbone were constructed. Resulting viral pseudotypes were tested for neutralization by 15 anti-V3 MAbs isolated from humans infected with viruses of either subtype B (anti-V3_B MAbs) or subtype A (anti-V3_A MAbs). Pseudovirions with the subtype B consensus V3 sequence were potently neutralized (IC₅₀ < 0.006 µg/ml) by all but one of these MAbs, while pseudovirions with V3 subtypes A, C, F, H, AG, and AE were generally neutralized more effectively by anti-V3_A MAbs than by anti-V3_B MAbs. A V1/V2-masked Env version of SF162 Env with the consensus B V3 sequence was also neutralized by these MAbs, although with considerably lower potency, while similarly masked chimeras with V3 sequences of subtype A, C, or AG were weakly neutralized by anti-V3_A MAbs but not by anti-V3_B MAbs. Mutations in the V1/V2 domain of YU-2 Env increased the sensitivity of this highly resistant Env to a pool of anti-V3_B MAbs several thousand-fold. These results demonstrated (i) the exceptional sensitivity of representative V3 domains of multiple subtypes to neutralization in the absence of epitope masking, (ii) the broader neutralizing activity of anti-V3_A MAbs for viruses containing diverse V3 sequences, and (iii) the generality and dominant effect of V1/V2 masking on restriction of V3-mediated neutralization.

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