Structural evidence for a bifurcated mode of action in the antibody-mediated neutralization of hepatitis C virus

被引：45

作者：

Deng, Lu ^{[1
]}

Zhong, Lilin ^{[1
]}

Struble, Evi ^{[1
]}

Duan, Hongying ^{[2
]}

Ma, Li ^{[1
]}

Harman, Christine ^{[1
]}

Yan, Hailing ^{[1
]}

Virata-Theimer, Maria Luisa ^{[1
]}

Zhao, Zhong ^{[1
]}

Feinstone, Stephen ^{[2
]}

Alter, Harvey ^{[3
]}

Zhang, Pei ^{[1
]}

机构：

[1] US FDA, Div Hematol, Off Blood Res & Review, Bethesda, MD 20892 USA

[2] US FDA, Div Viral Prod, Off Vaccine Res & Review, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA

[3] NIH, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2013年 / 110卷 / 18期

基金：

美国国家卫生研究院;

关键词：

MONOCLONAL-ANTIBODIES; INFECTION; E2; CHIMPANZEES; EPITOPES; VACCINE;

D O I：

10.1073/pnas.1305306110

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Hepatitis C virus (HCV) envelope glycoprotein E2 has been considered as a major target for vaccine design. Epitope II, mapped between residues 427-446 within the E2 protein, elicits antibodies that are either neutralizing or nonneutralizing. The fundamental mechanism of antibody-mediated neutralization at epitope II remains to be defined at the atomic level. Here we report the crystal structure of the epitope II peptide in complex with a monoclonal antibody (mAb#8) capable of neutralizing HCV. The complex structure revealed that this neutralizing antibody engages epitope II via interactions with both the C-terminal a-helix and the N-terminal loop using a bifurcated mode of action. Our structural insights into the key determinants for the antibody-mediated neutralization may contribute to the immune prophylaxis of HCV infection and the development of an effective HCV vaccine.

引用

页码：7418 / 7422

页数：5

共 26 条

[1] Hepatitis C: The End of the Beginning and Possibly the Beginning of the End [J].

Alter, Harvey J. ;

Liang, T. Jake .

ANNALS OF INTERNAL MEDICINE, 2012, 156 (04) :317-U111

[2] Recovery, persistence, and sequelae in hepatitis C virus infection: A perspective on long-term outcome [J].

Alter, HJ ;

Seeff, LB .

SEMINARS IN LIVER DISEASE, 2000, 20 (01) :17-35

[3] THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].

BAILEY, S .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763

[4]

Centers for Disease Control and Prevention, 2012, CDC HLTH INF INT TRA

[5] A conserved Gly436-Trp-Leu-Ala-Gly-Leu-Phe-Tyr motif in hepatitis C virus glycoprotein E2 is a determinant of CD81 binding and viral entry [J].

Drummer, Heidi E. ;

Boo, Irene ;

Maerz, Anne L. ;

Poumbourios, Pantelis .

JOURNAL OF VIROLOGY, 2006, 80 (16) :7844-7853

[6] Amino Acid Residue-Specific Neutralization and Nonneutralization of Hepatitis C Virus by Monoclonal Antibodies to the E2 Protein [J].

Duan, Hongying ;

Kachko, Alla ;

Zhong, Lilin ;

Struble, Evi ;

Pandey, Shivani ;

Yan, Hailing ;

Harman, Christine ;

Virata-Theimer, Maria Luisa ;

Deng, Lu ;

Zhao, Zhong ;

Major, Marian ;

Feinstone, Stephen ;

Zhang, Pei .

JOURNAL OF VIROLOGY, 2012, 86 (23) :12686-12694

[7] Features and development of Coot [J].

Emsley, P. ;

Lohkamp, B. ;

Scott, W. G. ;

Cowtan, K. .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 2010, 66 :486-501

[8] Diagnosis, Management, and Treatment of Hepatitis C: An Update [J].

Ghany, Marc G. ;

Strader, Doris B. ;

Thomas, David L. ;

Seeff, Leonard B. .

HEPATOLOGY, 2009, 49 (04) :1335-1374

[9] Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus [J].

Giang, Erick ;

Dorner, Marcus ;

Prentoe, Jannick C. ;

Dreux, Marlene ;

Evans, Matthew J. ;

Bukh, Jens ;

Rice, Charles M. ;

Ploss, Alexander ;

Burton, Dennis R. ;

Law, Mansun .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2012, 109 (16) :6205-6210

[10] Prospects for prophylactic and therapeutic vaccines against the hepatitis C viruses [J].

Houghton, Michael .

IMMUNOLOGICAL REVIEWS, 2011, 239 :99-108

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