An envelope modification that renders a primary, neutralization-resistant clade B human immunodeficiency virus type 1 isolate highly susceptible to neutralization by sera from other clades.

Several studies have reported on the differential susceptibility to antibody-mediated neutralization between primary (PR) and laboratory-adapted (LA) human immunodeficiency virus type 1 (HIV-1) isolates (1, 2, 6, 23, 24, 32, 39, 40, 45), the latter being more susceptible than the former to neutralization. To a large extent, this difference is explained by a documented differential exposure of neutralization epitopes within oligomeric envelope structures of PR and LA isolates. Such epitopes are less exposed on PR isolates than LA isolates (1, 24, 36, 40). The identification of the regions that shield neutralization epitopes and the nature of the neutralization epitopes themselves on PR isolates should shed light on the mechanism(s) by which HIV evades neutralization by serum antibodies and greatly benefit the design of effective HIV envelope-based immunogens. It has been reported that simultaneous deletion of the V1 and V2 loops of the neutralization-sensitive LA isolate HIV-1IIIb increases even further its susceptibility to neutralization by certain monoclonal antibodies (MAbs) whose epitopes are located within the V3 loop, the CD4-binding site, and conserved gp120 regions (3). We previously reported that the individual deletion of the V1 (17 amino acids) and V2 (30 amino acids) loops of the PR, neutralization-resistant HIV-1 isolate SF162 (7, 35, 39) does not reduce the potential of the virus to replicate in peripheral blood mononuclear cells (PBMC) or alter the coreceptor function of the envelope protein (38). Immunochemical analysis of the two mutant envelopes revealed that the deleted V1 and V2 loop sequences differentially affect the exposure and conformation of specific gp120 epitopes. While deletion of the V2 loop affects the structure of certain complex epitopes which comprise elements of the CD4-binding site, deletion of the V1 loop alters the conformation and exposure of specific epitopes located in the V2 and V3 loops and the CD4-binding site. However, regardless of these specific structural changes, neither deletion alters the overall ability of the envelope to interact with CD4 or its ability to undergo conformational changes upon receptor binding (38). In this study, we examined whether individual partial deletion of the V1 or V2 loop exposes cryptic neutralization epitopes on the surface of SF162 virions. We show that the V2, but not the V1, loop deletion renders the virus, termed SF162ΔV2, highly susceptible to serum-mediated neutralization. Most importantly, SF162ΔV2 becomes neutralizable by sera obtained from patients infected not only with clade B HIV-1 isolates but also with clade A, C, D, E, and F HIV-1 isolates. The introduced V2 loop deletion does not destabilize the gp120-gp41 subunit association, and the virus remains as resistant to antibody-mediated gp120-virion dissociation as wild-type (wt) SF162. Based on these observations, we suggest that this particular V2 loop deletion unveils an envelope region rich in neutralization epitopes whose overall structure is conserved among PR isolates. Neutralization studies conducted with various anti-gp120 MAbs failed to identify the precise epitopes forming this region, but it appears that it comprises structural elements of the CD4-binding site and conserved regions of gp120.