Natively glycosylated HIV-1 Env structure reveals new mode for antibody recognition of the CD4-binding site.
HIV-1 vaccine design is informed by structural studies elucidating mechanisms by which broadly neutralizing antibodies (bNAbs) recognize and/or accommodate N-glycans on the trimeric envelope glycoprotein (Env). Variability in high-mannose and complex-type Env glycoforms leads to heterogeneity that usually precludes visualization of the native glycan shield. We present 3.5-Å- and 3.9-Å-resolution crystal structures of the HIV-1 Env trimer with fully processed and native glycosylation, revealing a glycan shield of high-mannose and complex-type N-glycans, which we used to define complete epitopes of two bNAbs. Env trimer was complexed with 10-1074 (against the V3-loop) and IOMA, a new CD4-binding site (CD4bs) antibody. Although IOMA derives from VH1-2*02, the germline gene of CD4bs-targeting VRC01-class bNAbs, its light chain lacks the short CDRL3 that defines VRC01-class bNAbs. Thus IOMA resembles 8ANC131-class/VH1-46-derived CD4bs bNAbs, which have normal-length CDRL3s. The existence of bNAbs that combine features of VRC01-class and 8ANC131-class antibodies has implications for immunization strategies targeting VRC01-like bNAbs.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
Harry B
HB
Gristick
Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, USA.
Lotta
L
von Boehmer
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
Anthony P
AP
West
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
Michael
M
Schamber
Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, USA.
Anna
A
Gazumyan
Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, USA.
Jovana
J
Golijanin
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Michael S
MS
Seaman
Department of Internal Medicine I, University Hospital of Cologne, Cologne, Germany.|German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany.
Gerd
G
Fätkenheuer
German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany.|Laboratory of Experimental Immunology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.|Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, Cologne, Germany.
Florian
F
Klein
Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, USA.|Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA.
Michel C
MC
Nussenzweig
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
Pamela J
PJ
Bjorkman
D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology; D015704:CD4 Antigens / Q000737:chemistry / Q000276:immunology*; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000032:analysis / Q000276:immunology; D006031:Glycosylation; D015483:HIV Antibodies / Q000737:chemistry / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D008358:Mannose / Q000032:analysis* / Q000276:immunology; D008958:Models, Molecular; D011134:Polysaccharides / Q000032:analysis* / Q000276:immunology; D011487:Protein Conformation; D055503:Protein Multimerization
D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D011134:Polysaccharides; D008358:Mannose