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Published on: September 16, 2010
Structural analysis of the human immunodeficiency virus-binding domain of CD4. Epitope mapping with site-directed
Q J Sattentau1, J Arthos, K Deen
1Academic Department of Genito Urinary Medicine, University College and Middlesex School of Medicine (UCMSM), London, UK.
Insights
The CD4 molecule
Area of Science:
- Immunology
- Virology
- Structural Biology
Background:
- CD4 is a T lymphocyte differentiation marker crucial for lymphocyte activation.
- CD4 serves as the primary receptor for the Human Immunodeficiency Virus (HIV).
- The HIV envelope glycoprotein gp120 binds to the N-terminal (V1) domain of CD4.
Purpose of the Study:
- To investigate the structural similarities between the CD4 V1 domain and immunoglobulin kappa chain V domains (V kappa).
- To map the epitopes of CD4 monoclonal antibodies (mAbs) to understand the CD4 structure.
- To assess the relevance of CD4 epitope mapping for HIV vaccine strategies.
Main Methods:
- Epitope mapping of 26 CD4 mAbs using crossblocking analysis.
- Localization of mAb binding sites using truncated, soluble CD4 proteins.
- Detailed mapping of V1 domain epitopes using 17 substitution mutants.
- Crossblocking studies with anti-idiotype antibodies to examine mAb specificities.
Main Results:
- The CD4 V1 domain exhibits structural homology with V kappa regions.
- Epitopes are primarily located in predicted exposed loops within the V1 domain.
- Mapping reveals that some epitopes span discontinuous residues, forming an immunoglobulin fold.
- Epitope locations align with complementarity-determining regions when CD4 V1 is compared to Ig V kappa chains.
Conclusions:
- The CD4 V1 domain possesses a V kappa-like structure, supporting its homology to immunoglobulin domains.
- Epitope mapping provides insights into the structural organization of the CD4 molecule.
- Findings are relevant for developing anti-idiotype antibody-based HIV vaccines and for studying CD4's role in T cell activation.
Abstract:
The CD4 molecule, a differentiation marker expressed primarily by T lymphocytes, plays an important role in lymphocyte activation. CD4 is also the receptor for HIV. A number of recent studies have localized the high affinity binding site of the HIV envelope glycoprotein, gp120, to the NH2-terminal (V1) domain of CD4, a region with sequence and predicted structural homology with Ig kappa chain V domains (V kappa). In this report, we show that V1 bears structural similarities with V kappa regions through detailed epitope mapping of 26 CD4 mAbs. The binding sites of these mAbs were initially defined relative to one another by crossblocking analysis and were then localized to specific domains of CD4 in blocking studies with truncated, soluble CD4 proteins. The epitopes within the V1 domain were mapped in detail with a panel of 17 substitution mutants, and the specificities of several mAbs that appear to recognize very similar epitopes were examined in crossblocking studies with anti-idiotype antibodies. The location of the epitopes is consistent with a V kappa-like structure of V1. Most of the epitopes lie within regions of predicted exposed loops. A number of these epitopes span discontinuous residues in the linear sequence that lies in close proximity in an Ig fold. Alignment of CD4 V1 with the Ig V kappa chains places these epitopes within stretches corresponding to the complimentarity-determining regions. This epitope analysis is relevant for a vaccine strategy for HIV based on anti-idiotype antibodies to CD4 mAbs and for studies with CD4 antibodies on the role of CD4 in T lymphocyte activation.
