Increasing the potency and breadth of an HIV antibody by using structure-based rational design.
Antibodies against the CD4 binding site (CD4bs) on the HIV-1 spike protein gp120 can show exceptional potency and breadth. We determined structures of NIH45-46, a more potent clonal variant of VRC01, alone and bound to gp120. Comparisons with VRC01-gp120 revealed that a four-residue insertion in heavy chain complementarity-determining region 3 (CDRH3) contributed to increased interaction between NIH45-46 and the gp120 inner domain, which correlated with enhanced neutralization. We used structure-based design to create NIH45-46(G54W), a single substitution in CDRH2 that increases contact with the gp120 bridging sheet and improves breadth and potency, critical properties for potential clinical use, by an order of magnitude. Together with the NIH45-46-gp120 structure, these results indicate that gp120 inner domain and bridging sheet residues should be included in immunogens to elicit CD4bs antibodies.
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Ron
R
Diskin
Johannes F
JF
Scheid
Paola M
PM
Marcovecchio
Anthony P
AP
West
Florian
F
Klein
Han
H
Gao
Priyanthi N P
PN
Gnanapragasam
Alexander
A
Abadir
Michael S
MS
Seaman
Michel C
MC
Nussenzweig
Pamela J
PJ
Bjorkman
D016915:AIDS Vaccines; D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000915:Antibody Affinity; D001665:Binding Sites; D015704:CD4 Antigens / Q000737:chemistry / Q000378:metabolism; D022801:Complementarity Determining Regions; D018360:Crystallography, X-Ray; D015483:HIV Antibodies / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D011487:Protein Conformation; D015202:Protein Engineering; D017434:Protein Structure, Tertiary
D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D022801:Complementarity Determining Regions; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007140:Immunoglobulin Fab Fragments; D007143:Immunoglobulin Heavy Chains; D050505:Mutant Proteins; C514793:gp120 protein, Human immunodeficiency virus 1