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Antigenic variations in the CD4 induced sites of the CCR5-tropic, pathogenic SHIVsf162p3 gp120 variants
Abstract:
In vivo passage of non-pathogenic, CCR5-tropic simian/human immunodeficiency virus (SHIV) - SHIVsf162 resulted in a pathogenic isolate, SHIVsf162p3. In an attempt to characterize envelope (Env)-mediated properties that may contribute to its pathogenicity, major (P3 major) and minor (P3 minor) Env gp120 variants were cloned from the plasma of a SHIVsf162p3-infected animal, and expressed in the context of luciferase reporter viruses. Entry mediated by these envelopes and susceptibility to neutralization by CD4 induced-site (CD4i) antibodies (MAbs) was analyzed in comparison to parental SF162. Sequence analysis revealed that the P3 major and minor variant Envs contained 14 and 17 amino acid changes, respectively, compared with SF162. The rank order of entry mediated by the three envelopes was P3 major > SF162 > P3 minor, whereas the reverse order was observed for susceptibility to neutralization by CD4i MAbs. Since CD4i epitopes overlap the coreceptor (CoR) binding site, these findings suggest that the amino acid changes accumulated upon in vivo passage of SHIVsf162 result in Env gp120 structural rearrangements that modulate the exposure and/or conformation of the CoR binding site. This, in turn, led to increased entry and infectivity of the P3 major variant and may be responsible, in part, for the enhanced pathogenicity of SHIVsf162p3.
Insights
Simian/human immunodeficiency virus (SHIV) evolution increased pathogenicity by altering its envelope (Env) protein. These changes enhanced viral entry and infectivity, potentially explaining increased disease severity.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Non-pathogenic simian/human immunodeficiency virus (SHIV)-SHIVsf162 acquired pathogenicity after in vivo passage, becoming SHIVsf162p3.
- Understanding the envelope (Env) protein's role in SHIV pathogenicity is crucial for developing effective interventions.
Purpose of the Study:
- To characterize Env-mediated properties contributing to SHIVsf162p3 pathogenicity.
- To analyze the relationship between Env structure, viral entry, and neutralization susceptibility.
Main Methods:
- Cloning and expression of major (P3 major) and minor (P3 minor) Env gp120 variants from SHIVsf162p3 plasma.
- Utilizing luciferase reporter viruses to assess viral entry mediated by different Env variants.
- Analyzing neutralization susceptibility to CD4-induced (CD4i) antibodies (MAbs) against parental SF162 and variant Envs.
Main Results:
- P3 major and minor Envs exhibited 14 and 17 amino acid changes, respectively, compared to SF162.
- Viral entry followed the order: P3 major > SF162 > P3 minor.
- Neutralization susceptibility to CD4i MAbs showed the reverse order: P3 minor > SF162 > P3 major.
Conclusions:
- Accumulated amino acid changes in SHIV Env gp120 upon in vivo passage induce structural rearrangements.
- These rearrangements modulate the coreceptor (CoR) binding site, affecting exposure and/or conformation.
- Altered CoR binding site likely enhances viral entry and infectivity, contributing to SHIVsf162p3 pathogenicity.
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