TY - JOUR
T1 - Dengue virus neutralization is modulated by IgG antibody subclass and Fcγ receptor subtype
AU - Rodrigo, W. W.Shanaka I.
AU - Block, Olivia K.T.
AU - Lane, Christopher
AU - Sukupolvi-Petty, Soila
AU - Goncalvez, Ana P.
AU - Johnson, Syd
AU - Diamond, Michael S.
AU - Lai, Ching Juh
AU - Rose, Robert C.
AU - Jin, Xia
AU - Schlesinger, Jacob J.
N1 - Funding Information:
We thank Lihua Rong and Danielle Alcena for expert technical assistance. The work was funded by grants from the Pediatric Dengue Vaccine Initiative of the International Vaccine Institute (TR 03/04 to J.J.S.; TR16 to X.J.) and the NIH (R01 AI073755 and U01AI77955 ) to M.S.D.
PY - 2009/11/25
Y1 - 2009/11/25
N2 - Severe dengue virus (DENV) infection is epidemiologically linked to pre-existing anti-DENV antibodies acquired by maternal transfer or primary infection. A possible explanation is that DENV immune complexes evade neutralization by engaging Fcγ receptors (FcγR) on monocytes, natural targets for DENV in humans. Using epitope-matched humanized monoclonal antibodies (mAbs) and stable FcγR-transfected CV-1 cells, we found that DENV neutralization by IgG1, IgG3, and IgG4 mAbs was enhanced in high-affinity FcγRIA transfectants and diminished in low-affinity FcγRIIA transfectants, whereas neutralization by IgG2 mAbs (low-affinity ligands for both FcγRs) was diminished equally. In FcγR-negative Vero cells, IgG3 mAbs exhibited the strongest neutralizing activity and IgG2, the weakest. Our results demonstrate that DENV neutralization is modulated by the Fc region in an IgG subclass manner, likely through effects on virion and FcγR binding. Thus, the IgG antibody subclass profile generated by DENV infection or vaccination may independently influence the magnitude of the neutralizing response.
AB - Severe dengue virus (DENV) infection is epidemiologically linked to pre-existing anti-DENV antibodies acquired by maternal transfer or primary infection. A possible explanation is that DENV immune complexes evade neutralization by engaging Fcγ receptors (FcγR) on monocytes, natural targets for DENV in humans. Using epitope-matched humanized monoclonal antibodies (mAbs) and stable FcγR-transfected CV-1 cells, we found that DENV neutralization by IgG1, IgG3, and IgG4 mAbs was enhanced in high-affinity FcγRIA transfectants and diminished in low-affinity FcγRIIA transfectants, whereas neutralization by IgG2 mAbs (low-affinity ligands for both FcγRs) was diminished equally. In FcγR-negative Vero cells, IgG3 mAbs exhibited the strongest neutralizing activity and IgG2, the weakest. Our results demonstrate that DENV neutralization is modulated by the Fc region in an IgG subclass manner, likely through effects on virion and FcγR binding. Thus, the IgG antibody subclass profile generated by DENV infection or vaccination may independently influence the magnitude of the neutralizing response.
KW - Dengue virus
KW - Fc receptor
KW - Humanized monoclonal antibody
KW - Virus neutralization
UR - https://www.scopus.com/pages/publications/70449095877
U2 - 10.1016/j.virol.2009.09.024
DO - 10.1016/j.virol.2009.09.024
M3 - Article
C2 - 19833371
AN - SCOPUS:70449095877
SN - 0042-6822
VL - 394
SP - 175
EP - 182
JO - Virology
JF - Virology
IS - 2
ER -