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. 2004 Mar;78(5):2394-404.
doi: 10.1128/jvi.78.5.2394-2404.2004.

The v3 loop is accessible on the surface of most human immunodeficiency virus type 1 primary isolates and serves as a neutralization epitope

Miroslaw K Gorny  1 , Kathy Revesz, Constance Williams, Barbara Volsky, Mark K Louder, Christopher A Anyangwe, Chavdar Krachmarov, Samuel C Kayman, Abraham Pinter, Arthur Nadas, Phillipe N Nyambi, John R Mascola, Susan Zolla-Pazner
Affiliations

The v3 loop is accessible on the surface of most human immunodeficiency virus type 1 primary isolates and serves as a neutralization epitope

Miroslaw K Gorny et al. J Virol. 2004 Mar.

Abstract

Antibodies (Abs) against the V3 loop of the human immunodeficiency virus type 1 gp120 envelope glycoprotein were initially considered to mediate only type-specific neutralization of T-cell-line-adapted viruses. However, recent data show that cross-neutralizing V3 Abs also exist, and primary isolates can be efficiently neutralized with anti-V3 monoclonal Abs (MAbs). The neutralizing activities of anti-V3 polyclonal Abs and MAbs may, however, be limited due to antigenic variations of the V3 region, a lack of V3 exposure on the surface of intact virions, or Ab specificity. For clarification of this issue, a panel of 32 human anti-V3 MAbs were screened for neutralization of an SF162-pseudotyped virus in a luciferase assay. MAbs selected with a V3 fusion protein whose V3 region mimics the conformation of the native virus were significantly more potent than MAbs selected with V3 peptides. Seven MAbs were further tested for neutralizing activity against 13 clade B viruses in a single-round peripheral blood mononuclear cell assay. While there was a spectrum of virus sensitivities to the anti-V3 MAbs observed, 12 of the 13 viruses were neutralized by one or more of the anti-V3 MAbs. MAb binding to intact virions correlated significantly with binding to solubilized gp120s and with the potency of neutralization. These results demonstrate that the V3 loop is accessible on the native virus envelope, that the strength of binding of anti-V3 Abs correlates with the potency of neutralization, that V3 epitopes may be shared rather than type specific, and that Abs against the V3 loop, particularly those targeting conformational epitopes, can mediate the neutralization of primary isolates.

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Figures

FIG. 1.
FIG. 1.
Neutralization (A and C) and binding (B and D) curves for a panel of 32 human anti-V3 MAbs against psSF162 and gp120SF162 protein. psSF162 is the pNL4-3 luc virus pseudotyped with SF162 env. The human MAbs tested were selected either with V3-FP or gp120 (A and B) or with V3 peptides (C and D). The curves representing MAbs with neutralizing activities above 50% neutralization are shown in red, and those with activities below 50% neutralization are shown in blue. Data for the irrelevant antiparvovirus MAb 1418 (negative control) are shown in green.
FIG. 2.
FIG. 2.
Neutralization of psSF162 (A) and binding activity of MAbs to gp120SF162 (B). The geometric mean of the 50% neutralization dose and 50% maximal binding values for MAbs selected with V3-FPs or gp120 (•; 0.06 and 0.04 μg of MAb/ml, respectively) were significantly lower than the respective values for MAbs selected with V3 peptides (○; 0.40 and 0.32 μg of MAb/ml).
FIG. 3.
FIG. 3.
Linear regression analysis of percent neutralization of psSF162 versus the logarithm of 50% maximal MAb binding to gp120SF162. The best-fit regression line (solid line) and the 95% prediction interval (dashed lines) are shown. The data enclosed by the latter are expected to include 95% of all data points.
FIG. 4.
FIG. 4.
Titration curves for the binding of eight MAbs to 13 intact virions. The MAbs were tested at concentrations ranging from 0.0001 to 10.0 μg/ml and virus was added to all wells at a constant concentration of 100 ng of p24/ml. The amounts of virus bound by MAbs are represented by the picograms of p24 per milliliter released by detergent treatment of bound virus. The binding curves for neutralizing MAbs (as defined in Table 2) are shown in red, those for nonneutralizing MAbs are blue, and those for the negative control MAb 1418 are green.
FIG. 5.
FIG. 5.
Half-maximal binding of MAbs to intact virions. The logarithms of the half-maximal values (micrograms of MAb/ml) calculated from the binding curves shown in Fig. 4 are shown for each of 13 virus isolates, with mean values shown as solid lines.
FIG. 6.
FIG. 6.
Linear regression analyses of neutralization and virus binding data for 90 MAb-virus combinations. The data analyzed were taken from Table 2 and Fig. 4 and 5. The analyses show the correlation between percent neutralization and either the log of 50% maximal binding (A) or virus binding at saturation (using 10 μg of MAb/ml) (B). Best-fit regression lines (solid lines) and 95% prediction intervals (dashed lines) are shown.
FIG. 7.
FIG. 7.
Correlation between MAb binding to detergent-solubilized gp120 and capture of intact virions by MAbs under Ab-saturating conditions (A) and between MAb binding to gp120 and percent neutralization at 50 μg of MAb/ml (B). The data analyzed were taken from Tables 2 and 4 and Fig. 4.
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