Structure of a clade C HIV-1 gp120 bound to CD4 and CD4-induced antibody reveals anti-CD4 polyreactivity.

Abstract

Strategies to combat HIV-1 require structural knowledge of envelope proteins from clade C viruses, the most common in the world. We present the first 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 non-self antigen, and with CD4, an auto-antigen. Binding studies using wild-type and mutant CD4 showed 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 suggested a role for the gp120 V1V2 loop in creating a high-affinity, but slow-forming, epitope for 21c after CD4 binds. This study represents the first visualization of a potentially autoreactive antibody Fab complexed with both self and non-self antigens.