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Truncated variants of gp120 bind CD4 with high affinity and suggest a minimum CD4 binding region
S R Pollard1, M D Rosa, J J Rosa
1Biogen Inc., Cambridge, MA.
The EMBO Journal
|February 1, 1992
Summary
Researchers identified key regions of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein, gp120, essential for binding to CD4. A smaller gp120 variant (ENV59) retains CD4 binding and may serve as an immunogen.
Area of Science:
- Virology
- Immunology
- Structural Biology
Background:
- The envelope glycoprotein gp120 is crucial for HIV-1 entry by binding to the CD4 receptor on host cells.
- Understanding the structural determinants of gp120-CD4 interaction is vital for developing effective HIV-1 therapeutics and vaccines.
Purpose of the Study:
- To delineate the minimal structural requirements of gp120 for high-affinity CD4 binding.
- To assess the immunogenic potential of a truncated gp120 variant lacking non-essential regions.
Main Methods:
- Site-directed mutagenesis was employed to create deletion variants of gp120.
- CD4 binding affinity of the gp120 variants was measured.
- Immunoprecipitation assays were performed using polyclonal antibodies to assess antigenicity.
Main Results:
- Deletion of N- and C-terminal residues, along with V1, V2, and V3 variable regions, resulted in a 287-amino acid variant (ENV59) that retained high-affinity CD4 binding.
- The ENV59 variant showed reduced recognition by polyclonal antibodies, suggesting the loss of immunodominant epitopes.
- Complementing co-expressed gp120 fragments and a circularly permuted molecule also bound CD4, providing insights into gp120 structure.
Conclusions:
- A significant portion of gp120, including variable regions, is dispensable for CD4 binding.
- The truncated gp120 variant ENV59 may be a promising immunogen candidate for eliciting antibodies against conserved HIV-1 epitopes.
- The structural data suggest potential proximity of gp120 termini or unconstrained folding of the N-terminus.