Antibody-dependent cellular cytotoxicity-mediating antibodies from an HIV-1 vaccine efficacy trial target multiple epitopes and preferentially use the VH1 gene family.
The ALVAC-HIV/AIDSVAX-B/E RV144 vaccine trial showed an estimated efficacy of 31%. RV144 secondary immune correlate analysis demonstrated that the combination of low plasma anti-HIV-1 Env IgA antibodies and high levels of antibody-dependent cellular cytotoxicity (ADCC) inversely correlate with infection risk. One hypothesis is that the observed protection in RV144 is partially due to ADCC-mediating antibodies. We found that the majority (73 to 90%) of a representative group of vaccinees displayed plasma ADCC activity, usually (96.2%) blocked by competition with the C1 region-specific A32 Fab fragment. Using memory B-cell cultures and antigen-specific B-cell sorting, we isolated 23 ADCC-mediating nonclonally related antibodies from 6 vaccine recipients. These antibodies targeted A32-blockable conformational epitopes (n = 19), a non-A32-blockable conformational epitope (n = 1), and the gp120 Env variable loops (n = 3). Fourteen antibodies mediated cross-clade target cell killing. ADCC-mediating antibodies displayed modest levels of V-heavy (VH) chain somatic mutation (0.5 to 1.5%) and also displayed a disproportionate usage of VH1 family genes (74%), a phenomenon recently described for CD4-binding site broadly neutralizing antibodies (bNAbs). Maximal ADCC activity of VH1 antibodies correlated with mutation frequency. The polyclonality and low mutation frequency of these VH1 antibodies reveal fundamental differences in the regulation and maturation of these ADCC-mediating responses compared to VH1 bNAbs.
Duke University Medical Center, Durham, North Carolina, USA. mattia.bonsignori@duke.edu
Mattia
M
Bonsignori
Justin
J
Pollara
M Anthony
MA
Moody
Michael D
MD
Alpert
Xi
X
Chen
Kwan-Ki
KK
Hwang
Peter B
PB
Gilbert
Ying
Y
Huang
Thaddeus C
TC
Gurley
Daniel M
DM
Kozink
Dawn J
DJ
Marshall
John F
JF
Whitesides
Chun-Yen
CY
Tsao
Jaranit
J
Kaewkungwal
Sorachai
S
Nitayaphan
Punnee
P
Pitisuttithum
Supachai
S
Rerks-Ngarm
Jerome H
JH
Kim
Nelson L
NL
Michael
Georgia D
GD
Tomaras
David C
DC
Montefiori
George K
GK
Lewis
Anthony
A
DeVico
David T
DT
Evans
Guido
G
Ferrari
Hua-Xin
HX
Liao
Barton F
BF
Haynes
D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity; D005260:Female; D050438:Genes, Immunoglobulin Heavy Chain; D015483:HIV Antibodies / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006805:Human Experimentation; D006801:Humans; D008297:Male
D016915:AIDS Vaccines; D015483:HIV Antibodies