Identification of human CD4 residues affecting class II MHC versus HIV-1 gp120 binding.
Interactions of CD4 with the class II major histocompatibility complex (MHC) are crucial during thymic ontogeny and subsequently for helper and cytotoxic functions of CD4+CD8- T lymphocytes. CD4 is the receptor for the T-lymphotropic human immunodeficiency virus and binds its envelope glycoprotein, gp120. The residues involved in gp120 binding have been localized to a region within the immunoglobulin-like domain I of CD4, which corresponds to CDR2 of an immunoglobulin variable region, but the CD4 residues important in MHC class II interaction have not been characterized. Here, using a cell-binding assay dependent specifically on the CD4-MHC class II association, we analyse the effects of mutations in CD4 on class II versus gp120 binding. Mutations in CDR2 that destroy gp120 binding affect CD4-MHC class II binding similarly. In addition, binding of soluble gp120 to CD4-transfected cells abrogates their ability to interact with class II-bearing B lymphocytes. In contrast, other mutations within domains I or II that have no effect on gp120 binding eliminate or substantially decrease class II interaction. Thus, the CD4 binding site for class II MHC is more complex than the gp120 binding site, possibly reflecting a broader area of contact with the former ligand and a requirement for appropriate juxtaposition of the two N-terminal domains. The ability of gp120 to inhibit the binding of class II MHC to CD4 could be important in disrupting normal T-cell physiology, acting both to inhibit immune responses and to prevent differentiation of CD4+CD8+ thymocytes into CD4+CD8- T lymphocytes.
Clayton
L K
LK
Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Sieh
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M
Pious
D A
DA
Reinherz
E L
EL
D000818:Animals; D000911:Antibodies, Monoclonal; D001402:B-Lymphocytes / Q000276:immunology; D015699:HIV Envelope Protein gp120; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009154:Mutation; D015728:Receptors, HIV; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012191:Retroviridae Proteins / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology
D000911:Antibodies, Monoclonal; D015699:HIV Envelope Protein gp120; D000949:Histocompatibility Antigens Class II; D015728:Receptors, HIV; D011991:Receptors, Virus; D012191:Retroviridae Proteins