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Characterization of CD4-induced epitopes on the HIV type 1 gp120 envelope glycoprotein recognized by neutralizing
Shi-Hua Xiang1, Najah Doka, Rabeéa K Choudhary
1Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, USA.
Insights
New CD4-induced (CD4i) antibodies targeting HIV-1 gp120 were identified. These antibodies block viral entry by binding to a conserved region overlapping the CCR5 receptor site.
Area of Science:
- Immunology
- Virology
- Structural Biology
Background:
- Human immunodeficiency virus type 1 (HIV-1) entry into host cells requires sequential binding of the envelope glycoprotein gp120 to CD4 and a chemokine receptor (e.g., CCR5).
- CD4 binding to gp120 exposes specific epitopes, known as CD4-induced (CD4i) epitopes, which can be targeted by neutralizing antibodies.
- CD4i antibodies have the potential to block HIV-1's interaction with chemokine receptors, thereby inhibiting viral entry.
Purpose of the Study:
- To identify and characterize novel CD4i antibodies against HIV-1 gp120.
- To determine the precise epitopes recognized by these new CD4i antibodies.
- To investigate the functional consequences of CD4i antibody binding on viral entry and neutralization.
Main Methods:
- Isolation and characterization of CD4i antibodies from an HIV-1-infected individual.
- Epitope mapping to identify the specific gp120 residues targeted by the antibodies.
- Inhibition assays to assess the impact of antibodies on gp120 binding to CD4 and chemokine receptors (CCR5).
- Neutralization assays using laboratory-adapted and primary HIV-1 isolates.
Main Results:
- Three novel CD4i antibodies were identified, recognizing a conserved gp120 beta-strand (residues 419-424).
- This epitope is critical for gp120 binding to the CCR5 chemokine receptor.
- All identified CD4i antibodies inhibited the binding of gp120-CD4 complexes to CCR5.
- Antibody binding and CD4 binding to gp120 were mutually inducing, suggesting recognition of a similar conformation.
- CD4i antibodies neutralized laboratory-adapted HIV-1 strains but showed limited activity against primary isolates.
Conclusions:
- All known CD4i antibodies target a common, conserved gp120 element.
- This conserved element overlaps with the CCR5 binding site on gp120.
- CD4i antibodies represent a potential therapeutic strategy by blocking HIV-1 entry via the CCR5 co-receptor.
Abstract:
The entry of human immunodeficiency virus (HIV-1) into target cells typically requires the sequential binding of the viral exterior envelope glycoprotein, gp120, to CD4 and a chemokine receptor. CD4 binding exposes gp120 epitopes recognized by CD4-induced (CD4i) antibodies, which can block virus binding to the chemokine receptor. We identified three new CD4i antibodies from an HIV-1-infected individual and localized their epitopes. These epitopes include a highly conserved gp120 beta-strand encompassing residues 419-424, which is also important for binding to the CCR5 chemokine receptor. All of the CD4i antibodies inhibited the binding of gp120-CD4 complexes to CCR5. CD4i antibodies and CD4 reciprocally induced each other's binding, suggesting that these ligands recognize a similar gp120 conformation. The CD4i antibodies neutralized laboratory-adapted HIV-1 isolates; primary isolates were more resistant to neutralization by these antibodies. Thus, all known CD4i antibodies recognize a common, conserved gp120 element overlapping the binding site for the CCR5 chemokine receptor.
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