Structural analysis of the unmutated ancestor of the HIV-1 envelope V2 region antibody CH58 isolated from an RV144 vaccine efficacy trial vaccinee.
Human monoclonal antibody CH58 isolated from an RV144 vaccinee binds at Lys169 of the HIV-1 Env gp120 V2 region, a site of vaccine-induced immune pressure. CH58 neutralizes HIV-1 CRF_01 AE strain 92TH023 and mediates ADCC against CD4 + T cell targets infected with CRF_01 AE tier 2 virus. CH58 and other antibodies that bind to a gp120 V2 epitope have a second light chain complementarity determining region (LCDR2) bearing a glutamic acid, aspartic acid (ED) motif involved in forming salt bridges with polar, basic side amino acid side chains in V2. In an effort to learn how V2 responses develop, we determined the crystal structures of the CH58-UA antibody unliganded and bound to V2 peptide. The structures showed an LCDR2 structurally pre-conformed from germline to interact with V2 residue Lys169. LCDR3 was subject to conformational selection through the affinity maturation process. Kinetic analyses demonstrate that only a few contacts were responsible for a 2000-fold increase in KD through maturation, and this effect was predominantly due to an improvement in off-rate. This study shows that preconformation and preconfiguration can work in concert to produce antibodies with desired immunogenic properties.
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
Nathan I
NI
Nicely
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
Kevin
K
Wiehe
Boston University Department of Microbiology, Boston, MA, USA.
Thomas B
TB
Kepler
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
Frederick H
FH
Jaeger
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
S Moses
SM
Dennison
Ministry of Public Health, Nonthaburi, Thailand.
Supachai
S
Rerks-Ngarm
Armed Forces Research Institute of Medical Sciences, Thailand.
Sorachai
S
Nitayaphan
Mahidol University, Bangkok, Thailand.
Punnee
P
Pitisuttithum
Mahidol University, Bangkok, Thailand.
Jaranit
J
Kaewkungwal
Henry Jackson Foundation HIV Program, US Military HIV Research Program, Bethesda, MD, USA.
Merlin L
ML
Robb
Armed Forces Research Institute of Medical Sciences, Thailand.
Robert J
RJ
O'Connell
US Military HIV Research Program (MHRP), Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Nelson L
NL
Michael
US Military HIV Research Program (MHRP), Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Jerome H
JH
Kim
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
Hua-Xin
HX
Liao
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
S
S
Munir Alam
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
Kwan-Ki
KK
Hwang
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
Mattia
M
Bonsignori
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.
Barton F
BF
Haynes
D016915:AIDS Vaccines / Q000276:immunology*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000915:Antibody Affinity / Q000276:immunology; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D018604:Epitope Mapping; D015483:HIV Antibodies / Q000276:immunology* / Q000302:isolation & purification*; D015488:HIV Antigens / Q000737:chemistry / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000235:genetics* / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011487:Protein Conformation; D016896:Treatment Outcome
D016915:AIDS Vaccines; D015483:HIV Antibodies; D015488:HIV Antigens; D015699:HIV Envelope Protein gp120; D010455:Peptides
Antibody maturation; Germline; Gp120; HIV-1; RV-144; Unmutated ancestor; V2