Amino Acid Residue-Specific Neutralization and Nonneutralization of Hepatitis C Virus by Monoclonal Antibodies to the E2 Protein

Duan, Hongying; Kachko, Alla; Zhong, Li; Struble, Evi; Pandey, Shivani; Yan, Hailing; Harman, Christine; Virata-Theimer, Maria Luisa; Deng, Lu; Zhao, Zhong; Major, Marian E.; Zhang, Pei

doi:10.1128/jvi.00994-12

Cited by 26 publications

(54 citation statements)

References 31 publications

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“…Residues Leu 441 and Phe 442 on the α-helix were identified as being particularly important for nonneutralizing antibodies mAbs#12 and -#50 (17). In the complex structure of mAb#8-epitope II, Leu 441 and Phe 442 are positioned near the edge of the mAb#8-binding groove, facing inward and interacting exclusively with CDR H2 via van der Waals contacts ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…A 17-mer synthetic peptide ( 430 NESLNTGWLAGLFYQHK 446 ) of epitope II, whose sequence was derived from the E2 sequence of HCV genotype 1a (H77) (17), was cocrystallized with the Fab fragment of the neutralizing antibody, mAb#8. The crystal structure of the complex was determined to 2.85-Å resolution ( Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…All of the mAbs we have examined bind epitope II with a distinct activity: mAbs#8 and -#41 are both neutralizing antibodies, mAbs#12 and -#50 are nonneutralizing antibodies, and mAb#12 has the additional ability to interfere with neutralization (17). We further showed that Trp 437 and Leu 438 are the core residues for antibody recognition, regardless of the neutralizing capability of the antibody, whereas Leu 441 is required for both nonneutralizing antibodies (mAbs#12 and -#50), and Phe 442 is only specific for the binding of mAb#50 (17). We thus hypothesized that the effectiveness of antibody-mediated neutralization of HCV could be deduced from the interactions between an antibody and a specific set of amino acid residues.…”

Section: H Epatitis C Virus (Hcv) Infection Is a Major Public Healthmentioning

confidence: 99%

“…Interestingly, naturally evoked antibodies and those produced in vitro that are specifically directed against a short peptide located in the E2 protein between residues 427-446, also known as epitope II, displayed one of three activities: virus neutralization, E2 binding but no neutralization, or interference with virus neutralization (15,16). To capture the full spectrum of antibody responses in hepatitis C patients, we have previously characterized biochemically a panel of murine monoclonal antibodies (mAbs) into these three categories (17). All of the mAbs we have examined bind epitope II with a distinct activity: mAbs#8 and -#41 are both neutralizing antibodies, mAbs#12 and -#50 are nonneutralizing antibodies, and mAb#12 has the additional ability to interfere with neutralization (17).…”

Section: H Epatitis C Virus (Hcv) Infection Is a Major Public Healthmentioning

confidence: 99%

“…To capture the full spectrum of antibody responses in hepatitis C patients, we have previously characterized biochemically a panel of murine monoclonal antibodies (mAbs) into these three categories (17). All of the mAbs we have examined bind epitope II with a distinct activity: mAbs#8 and -#41 are both neutralizing antibodies, mAbs#12 and -#50 are nonneutralizing antibodies, and mAb#12 has the additional ability to interfere with neutralization (17). We further showed that Trp 437 and Leu 438 are the core residues for antibody recognition, regardless of the neutralizing capability of the antibody, whereas Leu 441 is required for both nonneutralizing antibodies (mAbs#12 and -#50), and Phe 442 is only specific for the binding of mAb#50 (17).…”

Section: H Epatitis C Virus (Hcv) Infection Is a Major Public Healthmentioning

confidence: 99%

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

Deng¹,

Zhong²,

Struble³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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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 α-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.H epatitis C virus (HCV) infection is a major public health problem with an estimated 170 million people infected worldwide (1). HCV is transmitted primarily through direct contact with the blood or other bodily fluids of an infected individual. Although acute hepatitis C is typically mild or even subclinical, the infection becomes chronic in more than 75% of those infected (2, 3). Patients with chronic HCV infection have a high risk of developing cirrhosis and, in some cases, hepatocellular carcinoma (2, 3).Significant advances have been made in the treatment of hepatitis C with the recent introduction of HCV-specific protease and polymerase inhibitors; sustained virologic responses, tantamount to cure, can now be achieved in more than 70% of the most difficult to treat HCV genotype 1-infected patients (4). However, the use of such drugs for treatment is not economically or logistically feasible in most parts of the world; therefore, vaccine development remains an important goal for the global control of HCV infection. Thus far, no HCV vaccine formulation has been able to induce sterilizing immunity, but a recombinant envelope protein vaccine has significantly reduced the rate of chronic HCV infection in a chimpanzee model (5). Thus, designing a vaccine that successfully elicits neutralizing antibodies remains a practical strategy to either prevent primary HCV infection or to reduce the frequency of progression from acute to chronic HCV infection (6).HCV envelope glycoprotein E2 has been studied extensively as a potential candidate for the immune prophylaxis of HCV infection and vaccine development. Several segments of the E2 protein have been identified as key components of conformational or linear epitopes that are critical to antibody-mediated neutralization of HCV in vitro (7-16). Interestingly, naturally evoked antibodies and those produced in vitro that are specifically directed against a short peptide located in the E2 protein between residues 427-446, also known as epitope II, displayed one of three activities: virus neutralization, E2 binding but no neutralization, or interference with virus neutralization (15, 16). To capture the f...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: H Epatitis C Virus (Hcv) Infection Is a Major Public Healthmentioning

confidence: 99%

Section: H Epatitis C Virus (Hcv) Infection Is a Major Public Healthmentioning

confidence: 99%

Section: H Epatitis C Virus (Hcv) Infection Is a Major Public Healthmentioning

confidence: 99%

See 3 more Smart Citations

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

Deng¹,

Zhong²,

Struble³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Antibodies to an interfering epitope in hepatitis C virus E2 can mask vaccine‐induced neutralizing activity

et al. 2015

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Hepatitis C virus (HCV) neutralization occurring at the E2 region 412–426 (EP-I) could be enhanced when antibodies directed specifically to the E2 region 434–446 (EP-II) were removed from serum samples of persistently infected patients and vaccinated chimpanzees, a phenomenon of so-called antibody interference. Here we show that this type of interference can be observed in individuals after immunization with recombinant E1E2 proteins. One hundred and twelve blinded serum samples from a Phase I, placebo-controlled, dose escalation trial using recombinant HCV E1E2 with MF59C.1 adjuvant in healthy HCV-negative adults were tested in ELISA for binding reactivity to peptides representing the E2 regions 412–426 (EP-I) and 434–446 (EP-II). All samples were subsequently tested for neutralizing activity using HCVcc 1a(H77)/2a chimera, HCVpp H77 and HCVpp HCV-1 after treatment to remove EP-II-specific antibodies or mock treatment with a control peptide. Among the 112 serum samples we found 22 double positive (EP-I and EP-II), 6 EP-II positive only, 14 EP-I positive only and 70 double negative. Depleting EP-II antibodies from double positive serum samples increased ID50 neutralizing antibody titers (up to 4.9-fold) in up to 72% of samples (p≤0.0005) contrasting with ID50 neutralization titer increases in 2 of 70 double negative samples (2.9%) (p>0.5). In addition, EP-I-specific antibody levels in serum samples showed a significant correlation with ID50 neutralization titers when EP-II antibodies were removed (p<0.0003). Conclusion These data show that antibodies to the region 434–446 are induced during immunization of individuals with recombinant E1E2 proteins and that these antibodies can mask effective neutralizing activity from EP-I-specific antibodies. Elicitation of EP-II-specific antibodies with interfering capacity should be avoided in producing an effective cross-neutralizing vaccine aimed at the HCV envelope proteins.

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The past, present and future of neutralizing antibodies for hepatitis C virus

2014

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Amino Acid Residue-Specific Neutralization and Nonneutralization of Hepatitis C Virus by Monoclonal Antibodies to the E2 Protein

Cited by 26 publications

References 31 publications

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

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

Antibodies to an interfering epitope in hepatitis C virus E2 can mask vaccine‐induced neutralizing activity

The past, present and future of neutralizing antibodies for hepatitis C virus

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