Identification of type-specific and cross-reactive neutralizing conformational epitopes on the major capsid protein of human papillomavirus type 31

Fleury, Maxime; Touzé, Antoine; Álvarez, Eva; Carpentier, Guillaume; Clavel, Christine; Vautherot, J-F; Coursaget, Pierre

doi:10.1007/s00705-006-0734-y

Cited by 34 publications

(34 citation statements)

References 46 publications

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“…Protection is mediated by neutralizing antibodies, and the work of several laboratories has identified cross-neutralizing epitopes (10)(11)(12)(13)(14)(15)(16)(17)(18). We have previously reported that monoclonal antibody RG-1, which is specific for residues 17-36 of L2 from HPV16, neutral-izes both HPV16 and HPV18 and protects naïve mice from challenge with HPV16 (12).…”

mentioning

confidence: 99%

Protection against heterologous human papillomavirus challenge by a synthetic lipopeptide vaccine containing a broadly cross-neutralizing epitope of L2

Alphs¹,

Gambhira²,

Karanam³

et al. 2008

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

138

143

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Persistent infection with the high-risk subset of genitotropic human papillomavirus (HPV) genotypes is a necessary cause of cervical cancer. Given the global burden of cervical cancer, a low-cost, broadly protective vaccine is needed. RG-1 is a crossneutralizing and protective monoclonal antibody that recognizes residues 17-36 of HPV16 minor capsid protein L2. Because this epitope is highly conserved in divergent HPV types, we determined whether vaccination with HPV16 L2 17-36 peptide is broadly protective. The peptide was administered to BALB/c mice three times at monthly intervals, either alone or in the context of a synthetic lipopeptide vaccine candidate (P25-P2C-HPV) produced by linkage of the HPV peptide with a broadly recognized T helper epitope (P25) and the Toll-like receptor-2 (TLR2) ligand dipalmitoyl-S-glyceryl cysteine (P2C). In contrast to vaccination with the L2 17-36 peptide or P25-P2C alone, a potent L2-specific antibody response was generated to the P25-P2C-HPV lipopeptide when delivered either s.c. or intranasally. Sera from mice vaccinated with the P25-P2C-HPV lipopeptide neutralized not only HPV16 pseudovirions but also other evolutionarily divergent oncogenic genital (HPV18, HPV45) and cutaneous (HPV5, BPV1) types. The L2-specific antibody response depended on MHC class II, CD40, and MyD88 signaling. Additionally, vaccination with the P25-P2C-HPV lipopeptide protected mice from homologous challenge with HPV16 pseudovirions at cutaneous and genital sites and heterologous challenge with HPV45 pseudovirions. If provided in the appropriate context, therefore, HPV16 L2 17-36 might be used in a totally synthetic cross-protective HPV vaccine. G enitotropic human papillomavirus (HPV) infections are considered the most common sexually transmitted infection in the United States (1). The major manifestations of anogenital HPV include genital warts (condyloma acuminatum) and anogenital intraepithelial neoplasia. If left untreated, a small fraction of persistent high-risk HPV infections progresses to cancer. The presence of HPV DNA has been reported in 99.7% of cervical carcinomas worldwide, indicating that HPV infection is a necessary cause of this cancer and that this disease can be prevented by prophylactic HPV vaccination (2).Approximately 35 of the Ͼ100 subtypes of HPV are specific for the anogenital epithelium and have varying potentials for malignant transformation (3). Of the 15 oncogenic genital HPV types, HPV16 is the most common, followed by HPV18 and HPV45 (contributing Ϸ50%, 20%, and 10%, respectively, of cervical cancer cases worldwide). Public health efforts have successfully reduced the incidence and mortality of cervical cancer with the implementation of cervical cytology screening programs. Women who do not undergo regular screening account for most of the patients with invasive cancers (4), and cervical cancer remains the second most common cause of cancer death in women worldwide and the most prevalent cancer in women of sub-Saharan Africa, Central America, south-central Asia, and Me...

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mentioning

confidence: 99%

Protection against heterologous human papillomavirus challenge by a synthetic lipopeptide vaccine containing a broadly cross-neutralizing epitope of L2

Alphs¹,

Gambhira²,

Karanam³

et al. 2008

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

138

143

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“…HPV31 L1 MAbs against immunogens representing the HPV31 reference sequence (GenBank accession number J04353) were previously generated (39). The majority of MAbs were raised against L1L2 VLPs; the exceptions were MAbs 31.D24 and 31.A19, where L1 VLP immunogens were used.…”

Section: Resultsmentioning

confidence: 99%

“…*, P Ͻ 0.05; **, P Ͻ 0.01; NS, no significant difference (P Ͼ 0.05). a Epitope location, structure (C, conformational; L, linear), specificity (TS, type specific; XR, cross-reactive), and MAb neutralizing potential were taken from the work of Fleury et al (39). -, MAbs for which binding or neutralization concentrations could not be determined at the highest input concentrations (by ELISA, 250 g/ml for all MAbs except 31.D24, for which the highest input concentration was 20 g/ml, and by neutralization assay, 125 g/ml for all MAbs except 31.D24, for which the highest input concentration was 10 g/ml).…”

Section: Discussionmentioning

confidence: 99%

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Naturally Occurring Capsid Protein Variants of Human Papillomavirus Genotype 31 Represent a Single L1 Serotype

Bissett

Godi

Fleury

et al. 2015

J Virol

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We investigated naturally occurring variation within the major (L1) and minor (L2) capsid proteins of oncogenic human papillomavirus (HPV) genotype 31 (HPV31) to determine the impact on capsid antigenicity. L1L2 pseudoviruses (PsVs) representing the three HPV31 variant lineages, variant lineages A, B, and C, exhibited comparable particle-to-infectivity ratios and morphologies. Lineage-specific L1L2 PsVs demonstrated subtle differences in susceptibility to neutralization by antibodies elicited following vaccination or preclinical L1 virus-like particle (VLP) immunization or by monoclonal antibodies; however, these differences were generally of a low magnitude. These data indicate that the diagnostic lineage-specific single nucleotide polymorphisms within the HPV31 capsid genes have a limited effect on L1 antibody-mediated neutralization and that the three HPV31 variant lineages belong to a single L1 serotype. These data contribute to our understanding of HPV L1 variant antigenicity. IMPORTANCEThe virus coat (capsid) of the human papillomavirus contains major (L1) and minor (L2) capsid proteins. These proteins facilitate host cell attachment and viral infectivity and are the targets for antibodies which interfere with these events. In this study, we investigated the impact of naturally occurring variation within these proteins upon susceptibility to viral neutralization by antibodies induced by L1 VLP immunization. We demonstrate that HPV31 L1 and L2 variants exhibit similar susceptibility to antibody-mediated neutralization and that for the purposes of L1 VLP-based vaccines, these variant lineages represent a single serotype. Human papillomaviruses (HPVs) have a double-stranded DNA genome of approximately 8 kb which is replicated via host cell polymerases with an error rate of ca. 2 ϫ 10 Ϫ8 base substitutions per site per year (1), substantially lower than that found in the majority of single-stranded RNA viruses (ca. 1 ϫ 10 Ϫ3 base substitutions per site per year) (2). Despite the low evolutionary rate of the HPV genome, variants have arisen over time, leading to the generation of distinct intragenotype lineages classified by a sequence difference of 1 to 10% across the whole genome (3). The single nucleotide polymorphisms (SNPs) that allow segregation of these variants into distinct lineages can be found in each gene/ region, with the highest number accumulating in the noncoding regions (NCR1, NCR2, and URR) and the lowest number accumulating in structural (L1 and L2) genes (4).The HPV structural genes encode the major (L1) and minor (L2) proteins that form the nonenveloped icosahedral viral capsid, which comprises 72 pentameric L1 capsomers, and each capsomer has an upper estimate of one L2 protein (5). The L1 protein mediates attachment to host cells (6), while the L2 protein is essential for subsequent viral infectivity (7).The humoral immune response following natural HPV infection predominately targets conformational epitopes on the surface-exposed loop regions of the L1 protein (8, 9). Seroconvers...

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“…The rim of the pentamer pocket is extremely variable contrary to its floor. With a few exceptions, all HPV-neutralizing monoclonal antibodies analyzed so far are type-specific and recognize conformational epitopes within these surface-exposed hyper variable loops (Pastrana et al, 2004;Fleury et al, 2006). HPV16 and HPV11 VLPs epitopes recognized by neutralizing mAbs are shown on Fig.…”

Section: Introductionmentioning

confidence: 99%

Plant Production of Vaccine Against HPV: A New Perspectives

Šmídková¹,

Holá²,

Brouzdová³

et al. 2012

Human Papillomavirus and Related Diseases - From Bench to Bedside - A Clinical Perspective

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Identification of type-specific and cross-reactive neutralizing conformational epitopes on the major capsid protein of human papillomavirus type 31

Cited by 34 publications

References 46 publications

Protection against heterologous human papillomavirus challenge by a synthetic lipopeptide vaccine containing a broadly cross-neutralizing epitope of L2

Protection against heterologous human papillomavirus challenge by a synthetic lipopeptide vaccine containing a broadly cross-neutralizing epitope of L2

Naturally Occurring Capsid Protein Variants of Human Papillomavirus Genotype 31 Represent a Single L1 Serotype

Plant Production of Vaccine Against HPV: A New Perspectives

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