Abstract
BackgroundThe 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.MethodsHIV-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 (IC50), and was statistically assessed based on the area under the neutralization titration curves (AUC).ResultsUsing AUC analyses, statistically significant neutralization was observed by ≥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 ≥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 ≥1 anti-V3 mAbs. Each anti-V3 mAb tested was able to neutralize 28–42% of the psVs tested. By IC50 criteria, 40/98 (41%) psVs were neutralized by ≥1 anti-V3 mAbs.ConclusionsUsing 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.
Highlights
Gp120, the surface subunit of the HIV-1 envelope (Env) glycoprotein, is a critical target for antibodies (Abs) that neutralize the virus and prevent infection
In the first set of experiments, six of the anti-V3 monoclonal Abs (mAbs) (2191, 2219, 2557, 2558, 3074, and 3869) were tested against a panel of 57 psVs prepared by Monogram Biosciences, Inc. to express Env populations from patients’ plasma viruses when infection was due to HIV-1 subtypes A, B, C, or D; anti-V3 mAb 447 was tested against a subset of 26 psVs from this same panel
The target cell line used in this set of experiments was CD4+CCR5+CXCR4+ U87
Summary
Gp120, the surface subunit of the HIV-1 envelope (Env) glycoprotein, is a critical target for antibodies (Abs) that neutralize the virus and prevent infection (reviewed in [1]). Gp120 serves as the virus attachment protein by binding to CD4 and the chemokine receptors CCR5 or CXCR4 Because of these crucial functions in the virus infectious process, it is logical that gp120 is a desired target for neutralizing Abs. gp120 displays astonishing agility in evading Ab neutralization [2,3,4,5,6]. Structural and immunochemical data suggest, that V3 contains conserved elements which explain its role in binding to virus coreceptors 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
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