Crystal structure of HIV-1 primary receptor CD4 in complex with a potent antiviral antibody.
Ibalizumab is a humanized, anti-CD4 monoclonal antibody. It potently blocks HIV-1 infection and targets an epitope in the second domain of CD4 without interfering with immune functions mediated by interaction of CD4 with major histocompatibility complex (MHC) class II molecules. We report here the crystal structure of ibalizumab Fab fragment in complex with the first two domains (D1-D2) of CD4 at 2.2 Å resolution. Ibalizumab grips CD4 primarily by the BC-loop (residues 121-125) of D2, sitting on the opposite side of gp120 and MHC-II binding sites. No major conformational change in CD4 accompanies binding to ibalizumab. Both monovalent and bivalent forms of ibalizumab effectively block viral infection, suggesting that it does not need to crosslink CD4 to exert antiviral activity. While gp120-induced structural rearrangements in CD4 are probably minimal, CD4 structural rigidity is dispensable for ibalizumab inhibition. These results could guide CD4-based immunogen design and lead to a better understanding of HIV-1 entry.
Division of Molecular Medicine, Children's Hospital, and Department of Pediatrics, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02115, USA.
Michael M
MM
Freeman
Michael S
MS
Seaman
Sophia
S
Rits-Volloch
Xinguo
X
Hong
Chia-Ying
CY
Kao
David D
DD
Ho
Bing
B
Chen
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism; D000914:Antibodies, Viral / Q000737:chemistry* / Q000378:metabolism; D000936:Antigen-Antibody Complex / Q000737:chemistry*; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism; D015704:CD4 Antigens / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D018360:Crystallography, X-Ray; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D011991:Receptors, Virus / Q000737:chemistry / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D000936:Antigen-Antibody Complex; D000998:Antiviral Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D011991:Receptors, Virus; C481504:ibalizumab