Anti-V3 monoclonal antibodies display broad neutralizing activities against multiple HIV-1 subtypes

PLoS One. 2010 Apr 21;5(4):e10254. doi: 10.1371/journal.pone.0010254.

Abstract

Background: The V3 loop of the HIV-1 envelope (Env) glycoprotein gp120 was identified as the "principal neutralizing domain" of HIV-1, but has been considered too variable to serve as a neutralizing antibody (Ab) target. Structural and immunochemical data suggest, however, that V3 contains conserved elements which explain its role in binding to virus co-receptors despite its sequence variability. Despite this evidence of V3 conservation, the ability of anti-V3 Abs to neutralize a significant proportion of HIV-1 isolates from different subtypes (clades) has remained controversial.

Methods: HIV-1 neutralization experiments were conducted in two independent laboratories to test human anti-V3 monoclonal Abs (mAbs) against pseudoviruses (psVs) expressing Envs of diverse HIV-1 subtypes from subjects with acute and chronic infections. Neutralization was defined by 50% inhibitory concentrations (IC(50)), and was statistically assessed based on the area under the neutralization titration curves (AUC).

Results: Using AUC analyses, statistically significant neutralization was observed by >or=1 anti-V3 mAbs against 56/98 (57%) psVs expressing Envs of diverse subtypes, including subtypes A, AG, B, C and D. Even when the 10 Tier 1 psVs tested were excluded from the analysis, significant neutralization was detected by >or=1 anti-V3 mAbs against 46/88 (52%) psVs from diverse HIV-1 subtypes. Furthermore, 9/24 (37.5%) Tier 2 viruses from the clade B and C standard reference panels were neutralized by >or=1 anti-V3 mAbs. Each anti-V3 mAb tested was able to neutralize 28-42% of the psVs tested. By IC(50) criteria, 40/98 (41%) psVs were neutralized by >or=1 anti-V3 mAbs.

Conclusions: Using standard and new statistical methods of data analysis, 6/7 anti-V3 human mAbs displayed cross-clade neutralizing activity and revealed that a significant proportion of viruses can be neutralized by anti-V3 Abs. The new statistical method for analysis of neutralization data provides many advantages to previously used analyses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antibodies, Monoclonal / immunology*
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Area Under Curve
  • Conserved Sequence / immunology
  • Cross Reactions / immunology*
  • Data Interpretation, Statistical
  • HIV Envelope Protein gp120 / immunology*
  • HIV Infections / immunology
  • HIV-1 / classification
  • HIV-1 / immunology*
  • Humans
  • Peptide Fragments / immunology*
  • Receptors, HIV

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • HIV Envelope Protein gp120
  • HIV envelope protein gp120 (305-321)
  • Peptide Fragments
  • Receptors, HIV