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An envelope modification that renders a primary, neutralization-resistant clade B human immunodeficiency virus type 1
1Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York 10021-6399, USA. leonidas@adarc.org
Abstract:
SF162 is a primary (PR), non-syncytium-inducing, macrophagetropic human immunodeficiency virus type 1 (HIV-1) clade B isolate which is resistant to antibody-mediated neutralization. Deletion of the first or second hypervariable envelope gp120 region (V1 or V2 loop, respectively) of this virus does not abrogate its ability to replicate in peripheral blood mononuclear cells and primary macrophages, nor does it alter its coreceptor usage profile. The mutant virus with the V1 loop deletion, SF162DeltaV1, remains as resistant to antibody-mediated neutralization as the wild-type virus SF162. In contrast, the mutant virus with the V2 loop deletion, SF162DeltaV2, exhibits enhanced susceptibility to neutralization by certain monoclonal antibodies whose epitopes are located within the CD4-binding site and conserved regions of gp120. More importantly, SF162DeltaV2 is now up to 170-fold more susceptible to neutralization than SF162 by sera collected from patients infected with clade B HIV-1 isolates. In addition, it becomes susceptible to neutralization by sera collected from patients infected with clade A, C, D, E, and F HIV-1 isolates. These findings suggest that the V2, but not the V1, loop of SF162 shields an as yet unidentified region of the HIV envelope rich in neutralization epitopes and that the overall structure of this region appears to be conserved among clade B, C, D, E, and F HIV-1 PR isolates.
Insights
The V2 loop of the SF162 human immunodeficiency virus type 1 (HIV-1) shields neutralization epitopes, unlike the V1 loop. Removing the V2 loop significantly increases HIV-1 susceptibility to antibody neutralization.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- SF162 is a primary, non-syncytium-inducing, macrophagetropic human immunodeficiency virus type 1 (HIV-1) clade B isolate.
- This isolate exhibits resistance to antibody-mediated neutralization.
Purpose of the Study:
- To investigate the role of the V1 and V2 loops of the HIV-1 SF162 envelope gp120 in antibody neutralization resistance.
- To determine if deletion of V1 or V2 loops affects viral replication or coreceptor usage.
Main Methods:
- Deletion mutagenesis of the V1 and V2 loops of the SF162 HIV-1 envelope gp120.
- Assessment of viral replication in peripheral blood mononuclear cells and primary macrophages.
- Evaluation of coreceptor usage profiles.
- Testing neutralization susceptibility using monoclonal antibodies and patient sera from various HIV-1 clades.
Main Results:
- Deletion of the V1 loop (SF162DeltaV1) did not alter neutralization resistance or coreceptor usage.
- Deletion of the V2 loop (SF162DeltaV2) resulted in enhanced susceptibility to neutralization by specific monoclonal antibodies targeting the CD4-binding site.
- SF162DeltaV2 showed increased susceptibility (up to 170-fold) to neutralization by clade B patient sera and became susceptible to sera from patients infected with HIV-1 clades A, C, D, E, and F.
Conclusions:
- The V2 loop of SF162 HIV-1 plays a crucial role in shielding neutralization epitopes within the gp120 envelope.
- The V1 loop does not appear to contribute significantly to the neutralization resistance of SF162.
- The findings suggest a conserved structure among different HIV-1 clades (B, C, D, E, F) in the region shielded by the V2 loop, offering potential targets for broader neutralization strategies.