Structure of a clade C HIV-1 gp120 bound to CD4 and CD4-induced antibody reveals anti-CD4 polyreactivity.
Strategies to combat HIV-1 require structural knowledge of envelope proteins from viruses in HIV-1 clade C, the most rapidly spreading subtype in the world. We present a crystal structure containing a clade C gp120 envelope. The structure, a complex between gp120, the host receptor CD4 and the CD4-induced antibody 21c, reveals that the 21c epitope involves contacts with gp120, a nonself antigen, and with CD4, an autoantigen. Binding studies using wild-type and mutant CD4 show that 21c Fab binds CD4 in the absence of gp120, and that binding of 21c to clade C and HIV-2 gp120s requires the crystallographically observed 21c-CD4 interaction. Additional binding data suggest a role for the gp120 V1V2 loop in creating a high-affinity, but slow-forming, epitope for 21c after CD4 binds. These results contribute to a molecular understanding of CD4-induced antibodies and provide the first visualization to our knowledge of a potentially autoreactive antibody Fab complexed with both self and nonself antigens.
Diskin
Ron
R
Division of Biology, California Institute of Technology, Pasadena, California, USA.
Marcovecchio
Paola M
PM
Bjorkman
Pamela J
PJ
D000914:Antibodies, Viral / Q000737:chemistry* / Q000276:immunology*; D015704:CD4 Antigens / Q000737:chemistry* / Q000276:immunology*; D002460:Cell Line; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D008958:Models, Molecular
D000914:Antibodies, Viral; D015704:CD4 Antigens; D000939:Epitopes; D015699:HIV Envelope Protein gp120