Induction of Cross-reactive Humoral Immune Response by Immunization with Mimotopes of the Hypervariable Region 1 of the Hepatitis C Virus

Roccasecca, RosaMaria; Folgori, Antonella; Ercole, Bruno Bruni; Puntoriero, Giulia; Lahm, Armin; Zucchelli, S.; Tafi, Rosalba; Pezzanera, Monica; Galfrè, G.; Tramontano, Anna; Mondelli, Mario U.; Pessi, Antonello; Nicosia, Alfredo; Cortese, Riccardo; Meola, Annalisa

doi:10.3109/08830180109043040

Cited by 11 publications

(10 citation statements)

References 16 publications

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“…Another phage peptide mimotope (sequence GLLVWSDEL) with a b12 binding motif of M/V SD ( represents an aromatic amino acid) was identified but was only able to elicit weakly gp120 reactive immune responses [83]. Thus, while peptide mimotopes for the b12 epitope have yielded limited results, peptide mimotopes have been shown in other systems to elicit both cross reactive and protective immune responses [38,39,270,271,285,286]. Again like outer domain constructs, peptide mimotopes will need to better mimic the b12 epitope for this strategy to succeed.…”

Section: Targeting the Cd4 Binding Sitementioning

confidence: 98%

Designing Immunogens to Elicit Broadly Neutralizing Antibodies to the HIV-1 Envelope Glycoprotein

Lin

Nara²

2007

CHR

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To date HIV-1 vaccines have not been able to elicit potent, long lasting, and broadly neutralizing antibodies to the virus. Our knowledge of HIV envelope glycoprotein (Env) structure/function and the existence of a handful of broadly neutralizing antibodies is guiding rational immunogen design. We review here the potential targets on the HIV Env (the glycan shield, the CD4 binding site, the coreceptor binding site, Env fusion intermediates, and the membrane proximal region) and their associated rational immunogen design strategies. Moreover, we discuss immune dampening and immune refocusing strategies designed to counter immunodominant, decoy responses generated by the virus. In this regard, an immunogen design strategy of "in vitro de-evolution" is presented, which begins to distill the HIV Env to its most critical, core functional domains. While we are beginning to have some understanding as to where we would like out immune system to go, we find that our immune repertoire may actually have limits that preclude successful completion of the task at hand. The repertoire limits appear to be a byproduct of autoantibody tolerance mechanisms and the complex structural requirements for effective, potent broadly neutralizing antibodies. Nevertheless, the hope is that through novel insights and creative solutions that we will be able to design immunogens capable of eliciting broadly neutralizing antibodies to the HIV envelope glycoprotein.

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Section: Targeting the Cd4 Binding Sitementioning

confidence: 98%

Designing Immunogens to Elicit Broadly Neutralizing Antibodies to the HIV-1 Envelope Glycoprotein

Lin

Nara²

2007

CHR

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“…This provided strong evidence in support of the contention that HCV variant selection is driven by immune pressure. Monoclonal antibodies (MAbs) generated after immunization of mice with peptides derived from a natural HVR1 sequence were observed to generate a neutralization response for several HVR1 sequences, attesting to the existence of conserved amino acid motifs among different variants (52). These findings suggest the possibility for an induction of a broadly cross-reactive immune response to HVR1 and that this mechanism can be used to generate protective immunity.…”

mentioning

confidence: 88%

“…A binding site for neutralizing antibodies has been identified in the HVR1 region (52). Interestingly, despite strong amino acid sequence variability, the chemicophysical properties and conformation of HVR1 are highly conserved (50).…”

mentioning

confidence: 99%

The Hypervariable Region 1 of the E2 Glycoprotein of Hepatitis C Virus Binds to Glycosaminoglycans, but This Binding Does Not Lead to Infection in a Pseudotype System

Basu¹,

Beyene²,

Meyer³

et al. 2004

J Virol

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The hypervariable region 1 (HVR1) of hepatitis C virus (HCV) E2 envelope glycoprotein is a 27-amino-acid sequence located at its N terminus. In this study, we investigated the functional role of HVR1 for interaction with the mammalian cell surface. The C-terminal truncated E2 glycoprotein was appended to a transmembrane domain and cytoplasmic tail of vesicular stomatitis virus (VSV) G protein for generation of the chimeric E2-G gene construct. A deletion of the HVR1 sequence from E2 was created for the construction of E2⌬HVR1-G. Pseudotype virus, generated separately by infection of a stable cell line expressing E2-G or E2⌬HVR1-G with a temperature-sensitive mutant of VSV (VSVts045), displayed unique functional properties compared to VSVts045 as a negative control. Virus generated from E2⌬HVR1-G had a reduced plaquing efficiency (ϳ50%) in HepG2 cells compared to that for the E2-G virus. Cells prior treated with pronase (0.5 U/ml) displayed a complete inhibition of infectivity of the E2⌬HVR1-G or E2-G pseudotypes, whereas heparinase I treatment (8 U/ml) of cells reduced 40% E2-G pseudotype virus titer only. E2⌬HVR1-G pseudotypes were not sensitive to heparin (6 to 50 g/ml) as an inhibitor of plaque formation compared to the E2-G pseudotype virus. Although the HVR1 sequence itself does not match with the known heparin-binding domain, a synthetic peptide representing 27 amino acids of the E2 HVR1 displayed a strong affinity for heparin in an enzyme-linked immunosorbent assay. This binding was competitively inhibited by a peptide from the V3 loop of a human immunodeficiency virus glycoprotein subunit (gp120) known to bind with cell surface heparin. Taken together, our results suggest that the HVR1 of E2 glycoprotein binds to the cell surface proteoglycans and may facilitate virus-host interaction for replication cycle of HCV.Hepatitis C virus (HCV) is a major causative agent of parentally transmitted hepatitis (9) and is associated with liver cirrhosis and hepatocellular carcinoma (1). Approximately 25% of infected individuals appear to clear viremia without therapeutic intervention (2, 31), and the mechanism leading to this natural resolution of HCV infection is not completely understood. However, the majority of HCV-infected individuals do not resolve infection, leading to the development of chronic hepatitis.The HCV genome is a linear, positive sense, single-stranded RNA molecule of ϳ9,500 nucleotides. It encodes a polyprotein precursor of ϳ3,000 amino acids (10). This polyprotein is cleaved by both host and viral proteases to generate several distinct polypeptides (24,29,36). The structural proteins, core, E1 and E2, of HCV physically interact and may have a role in virus assembly (4,11,36). The glycosylated polypeptides (E1 and E2) are most likely anchored onto the envelope lipid bilayer of the virus and facilitate virus entry by interaction with the cell surface. In vitro expression studies have suggested that the glycoproteins of HCV associate to form two types of complexes: (i) a heterodimer stabilized by no...

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“…To generate the Ad6/F78E2 662 vector, a human codon-optimized sequence coding for tissue plasminogen activator (tPA) leader sequence, F78, and E2 662 (cDNA of E2 protein truncated at 662 amino acids [aa]) from HCV strain T212 was cloned under the control of the human CMV promoter and BGH polyadenylation signal between two Ad6 flanking regions, creating pNEB/F78E2 662 plasmid. In both constructs the natural HVR1 sequence at the N terminus of E2 was replaced by an artificial mimotope, F78, which was previously shown to elicit cross-reactive antibodies to diverse HVR1 variants following immunization of mice and rabbits (27).…”

Section: Plasmid Constructionmentioning

confidence: 99%

Combined Adenovirus Vector and Hepatitis C Virus Envelope Protein Prime-Boost Regimen Elicits T Cell and Neutralizing Antibody Immune Responses

Chmielewska

Naddeo

Capone

et al. 2014

J Virol

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Despite the recent progress in the development of new antiviral agents, hepatitis C virus (HCV) infection remains a major global health problem, and there is a need for a preventive vaccine. We previously reported that adenoviral vectors expressing HCV nonstructural proteins elicit protective T cell responses in chimpanzees and were immunogenic in healthy volunteers. Furthermore, recombinant HCV E1E2 protein formulated with adjuvant MF59 induced protective antibody responses in chimpanzees and was immunogenic in humans. To develop an HCV vaccine capable of inducing both T cell and antibody responses, we constructed adenoviral vectors expressing full-length and truncated E1E2 envelope glycoproteins from HCV genotype 1b. Heterologous prime-boost immunization regimens with adenovirus and recombinant E1E2 glycoprotein (genotype 1a) plus MF59 were evaluated in mice and guinea pigs. Adenovirus prime and protein boost induced broad HCV-specific CD8 Hepatitis C virus (HCV) infection is a major global health problem affecting an estimated 170 million people worldwide, occurring among persons of all ages, genders, races, and regions of the world. Chronically infected subjects are at risk of developing progressive liver disease, including cirrhosis, and primary hepatocellular carcinoma (1). Although the recent introduction of directly acting antiviral drugs (DAAs) has improved therapy for chronic HCV and interferon (IFN)-free regimens are on the horizon (2), treatment success may be limited by a range of factors, including awareness of infection status, access to and cost of therapy, relative efficacy of different regimens for specific HCV genotypes, adverse effects, comorbidities (e.g., cirrhosis or HIV coinfection), and host factors. For these reasons, the development of a safe, effective, and affordable preventive vaccine against HCV is the optimal long-term goal to control the global epidemic (3).Approximately 20% of infected individuals clear the virus spontaneously, and resolution is associated with HLA type and with potent, multispecific, and long-lasting T cell responses (4). T cell depletion experiments with chimpanzees confirmed the essential role of cellular immunity in controlling HCV infection (5). Moreover, antibodies targeting the HCV envelope glycoproteins have been shown to neutralize infection in vitro (6, 7) and to protect against virus challenge in the human liver-Alb-uPA/SCID murine model (8)(9)(10). A recent report demonstrated that spontaneous clearance of HCV is associated with the early appearance of a broadly neutralizing antibody response (11). Recombinant E1E2 glycoproteins have been shown to induce cross-neutralizing antibody responses against het-

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Induction of Cross-reactive Humoral Immune Response by Immunization with Mimotopes of the Hypervariable Region 1 of the Hepatitis C Virus

Cited by 11 publications

References 16 publications

Designing Immunogens to Elicit Broadly Neutralizing Antibodies to the HIV-1 Envelope Glycoprotein

Designing Immunogens to Elicit Broadly Neutralizing Antibodies to the HIV-1 Envelope Glycoprotein

The Hypervariable Region 1 of the E2 Glycoprotein of Hepatitis C Virus Binds to Glycosaminoglycans, but This Binding Does Not Lead to Infection in a Pseudotype System

Combined Adenovirus Vector and Hepatitis C Virus Envelope Protein Prime-Boost Regimen Elicits T Cell and Neutralizing Antibody Immune Responses

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