The MHC-binding and gp120-binding functions of CD4 are separable.
CD4 is a cell surface glycoprotein that is thought to interact with nonpolymorphic determinants of class II major histocompatibility (MHC) molecules. CD4 is also the receptor for the human immunodeficiency virus (HIV), binding with high affinity to the HIV-1 envelope glycoprotein, gp120. Homolog-scanning mutagenesis was used to identify CD4 regions that are important in class II MHC binding and to determine whether the gp120 and class II MHC binding sites of CD4 are related. Class II MHC binding was abolished by mutations in each of the first three immunoglobulin-like domains of CD4. The gp120 binding could be abolished without affecting class II MHC binding and vice versa, although at least one mutation examined reduced both functions significantly. These findings indicate that, while there may be overlap between the gp120 and class II MHC binding sites of CD4, these sites are distinct and can be separated. Thus it should be possible to design CD4 analogs that can block HIV infectivity but intrinsically lack the ability to affect the normal immune response by binding to class II MHC molecules.
Lamarre
D
D
Laboratoire d'Immunologie, Institut de Recherches Cliniques de Montréal, Québec, Canada.
Ashkenazi
A
A
Fleury
S
S
Smith
D H
DH
Sekaly
R P
RP
Capon
D J
DJ
D000595:Amino Acid Sequence; D000818:Animals; D000954:Antigens, Surface; D001665:Binding Sites; D004274:DNA, Recombinant; D006678:HIV / Q000378:metabolism*; D015699:HIV Envelope Protein gp120; D006682:HLA-DP Antigens / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D006825:Hybridomas; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D015728:Receptors, HIV; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012191:Retroviridae Proteins / Q000276:immunology / Q000378:metabolism*; D012397:Rosette Formation; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014162:Transfection
D000954:Antigens, Surface; D004274:DNA, Recombinant; D015699:HIV Envelope Protein gp120; D006682:HLA-DP Antigens; D000949:Histocompatibility Antigens Class II; D015728:Receptors, HIV; D011991:Receptors, Virus; D012191:Retroviridae Proteins