Hybrid Papillomavirus L1 Molecules Assemble into Virus-like Particles That Reconstitute Conformational Epitopes and Induce Neutralizing Antibodies to Distinct HPV Types

Christensen, Neil D.; Cladel, Nancy M.; Reed, Cynthia A.; Budgeon, Lynn R.; Embers, Monica E.; Skulsky, Dee Marie; McClements, William L.; Ludmerer, Steven W.; Jansen, Kathrin U.

doi:10.1006/viro.2001.1220

Cited by 112 publications

(124 citation statements)

References 55 publications

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“…Similarly, the substitution at position 291 was immediately before the surface-exposed hypervariable residue 285 in the FG loop of HPV16, which has been implicated as an important residue for binding of a major neutralizing antibody. 34,35 The possible surface exposure of the adjacent substitution at residue 288 in HPV38 is difficult to predict since the FG loop of HPV38 contains an insertion of seven amino acids seven residues before this position, compared to that of HPV16.…”

Section: Complete Genome Of Hpv38b[fa125]mentioning

confidence: 99%

Subtype HPV38b[FA125] demonstrates heterogeneity of human papillomavirus type 38

Hazard

Eliasson

Dillner

et al. 2006

Intl Journal of Cancer

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The human papillomaviruses (HPVs) exist as more than 100 distinct types. While variants of HPV are common, only few HPV subtypes have been reported. HPV type 38 has been proposed to be associated with nonmelanoma skin cancer (NMSC), with reported prevalences of up to 55%. A subtype of HPV38 was cloned, completely sequenced and found to have a 96% sequence similarity to prototype HPV38 in the L1 open reading frame. The presence of prototype HPV38 and HPV38b[FA125] was examined in paired biopsies of tape-stripped skin lesions and healthy skin from 269 immunocompetent patients by real-time PCR. Prototype HPV38 and HPV38b[FA125] were present in seven (3%) and five (2%) lesions, respectively, in viral loads ranging from one copy per 150 cells to one copy per 70,000 cells. In summary, we found that HPV38 is heterogeneous and is one of so far only few HPVs that contain subtypes. The heterogeneity needs to be considered in studies of the biology of this virus. ' 2006 Wiley-Liss, Inc.Key words: HPV; subtype; nonmelanoma skin cancer; multiplyprimed rolling circle amplification Nonmelanoma skin cancers (NMSC) are the most prevalent malignancies in the Caucasian population 1 and an increase in prevalence has been seen in European countries during the last few years. 2 NMSC comprises basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCC has a relatively good prognosis, while SCC accounts for up to 20% of all deaths from skin cancer. 3 NMSC are often found on sun-exposed sites in patients with the rare inherited genetic disease epidermodysplasia verruciformis (EV). 4 These patients are highly susceptible to human papillomavirus (HPV) infections 5,6 mainly by the Beta-papillomaviruses, a phylogenetic subgroup of cutaneous HPVs (e.g., HPV5 and HPV8). 7 These HPV types are detectable in skin carcinomas, as well as in control specimens of healthy skin from the general population. [8][9][10][11][12] There are more than 100 different HPV types that have been completely sequenced. 7 In addition, there appears to exist about 100 additional putative HPV types, with sequence information so far available only from PCR amplimers. 8,[13][14][15][16] Variants of HPV types contain more than 98% sequence homology in the L1 open reading frame (ORF). 7 Variants is a common finding that appears to associate with ethnic groups and sometimes even with biologic behavior of the virus. 17,18 By contrast, subtypes containing 90-98% sequence homology in the L1 region are very rare, with HPV 68a/HPV68b, HPV46, HPV55 and HPV64 (now known to be subtypes, originally thought to be different viruses) being the only fully characterized examples. 7,17 Although the reasons for this are not known, existence of subtypes has profound implications for design of virus detection systems and for understanding of the biology of the viruses.Epidemiological studies have established a causal association between UV-radiation and NMSC, 3 but the role of HPV in these cancers remains to be elucidated.A recent study 19 has demonstrated that the early proteins E...

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Section: Complete Genome Of Hpv38b[fa125]mentioning

confidence: 99%

Subtype HPV38b[FA125] demonstrates heterogeneity of human papillomavirus type 38

Hazard

Eliasson

Dillner

et al. 2006

Intl Journal of Cancer

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“…Not only have structural alterations of HPV particles affected infectivity, but also they have altered the particle's function as an immunogen (Kirnbauer et al, 1992;Breitburd et al, 1995;White et al, 1999;Christensen et al, 2001;Yang et al, 2005). Specifically, global conformational changes in VLPs can change the immunoreactivity profile against a panel of conformationdependent neutralizing monoclonal antibodies (MAbs) (White et al, 1999;Christensen et al, 2001).…”

Section: Structural Alterations Affecting Functionmentioning

confidence: 99%

Section: Structural Alterations Affecting Functionmentioning

confidence: 99%

“…Specifically, global conformational changes in VLPs can change the immunoreactivity profile against a panel of conformationdependent neutralizing monoclonal antibodies (MAbs) (White et al, 1999;Christensen et al, 2001). For example, VLPs with a F50L substitution are not bound by the conformation-dependent MAbs, H16.V5 and H16.E70, while they are bound by MAbs that recognize surface linear epitopes (Christensen et al, 2001). Further, vaccination of mice with HPV16 VLPs containing the assembly-incompetent D223G, N327S, and F446S L1 substitutions failed to induce neutralizing antibodies, while HPV16 VLPs containing the assembly-competent D202H substitution led to the activation of bone-marrow-derived dendritic cells (BMDCs) and a potent L1-specific humoral response, but also failed to induce neutralizing antibodies.…”

Section: Structural Alterations Affecting Functionmentioning

confidence: 99%

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Replication and Assembly of Human Papillomaviruses

Conway

Meyers²

2009

J Dent Res

117

101

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Human papillomaviruses (HPVs) are small dsDNA tumor viruses, which are the etiologic agents of most cervical cancers and are associated with a growing percentage of oropharyngeal cancers. The HPV capsid is non-enveloped, having a T=7 icosahedral symmetry formed via the interaction among 72 pentamers of the major capsid protein, L1. The minor capsid protein L2 associates with L1 pentamers, although it is not known if each L1 pentamer contains a single L2 protein. The HPV life cycle strictly adheres to the host cell differentiation program, and as such, native HPV virions are only produced in vivo or in organotypic "raft" culture. Research producing synthetic papillomavirus particles-such as virus-like particles (VLPs), papillomavirus-based gene transfer vectors, known as pseudovirions (PsV), and papillomavirus genome-containing quasivirions (QV)-has bypassed the need for stratifying and differentiating host tissue in viral assembly and has allowed for the rapid analysis of HPV infectivity pathways, transmission, immunogenicity, and viral structure.

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“…The latter is due to the fact that neutralizing anti-L1 binds to surface loops on the viral capsids, which are highly heterogeneous among the different HPV types. [10][11][12] In fact, every HPV genotype analyzed to date represents a separate serotype, and, that is why, with very few exceptions, anti-L1 neutralizing antibodies are highly HPV-type specific. Combined with the observation that L1 is the most conserved papillomavirus protein, one can conclude that the escape of naturally existing neutralizing antibodies has been a major driving factor in the evolution of papillomaviruses.…”

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confidence: 99%

Natural variants in the major neutralizing epitope of human papillomavirus minor capsid protein L2

Seitz

Schmitt

Böhmer³

et al. 2012

Intl Journal of Cancer

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The amino terminus of the human papillomavirus minor capsid protein L2 contains a major cross-neutralizing epitope that provides the basis for the development of a broadly protective HPV vaccine. This attainable broad protection would eliminate one of the major drawbacks of the commercial L1-based prophylactic vaccines. In this study, we asked whether there are natural variants of the L2 cross-neutralizing epitope and if these variants provide means for immune escape from vaccineinduced anti-L2 antibodies. For this, we isolated in silico and in vitro, a total of 477 L2 sequences of HPV types 16, 18, 31, 45, 51, 52 and 58. We identified natural L2 epitope variants for HPV 18, 31, 45 and 51. To determine whether these variants escape L2-directed neutralization, we generated pseudovirions encompassing the natural variants and tested these in an in vitro neutralization assay using monoclonal and polyclonal antibodies. Our results indicate that natural variants of the L2 major neutralizing epitope are frequent among two different study populations from Germany and Mongolia and in the GenBank database. Of two identified HPV 31 L2 single amino acid variants, one could be neutralized well, while the other variant was neutralized very poorly. We also observed that single amino acid variants of HPV 18 and 45 are neutralized well while a HPV 18 double variant was neutralized at significantly lower rates, indicating that L2 variants have to be accounted for when developing HPV L2-based prophylactic vaccines.Human papillomaviruses (HPVs) are the causative agents for the development of cervical cancer. Close to 100% of tumors from the uterine cervix harbor sequences of HPVs; at least 15 different types are linked to cancer, and these are termed as ''oncogenic HPV types.'' 1 Worldwide, the 10 most frequently isolated HPV types in cervical cancer are HPV 16,18,33, 45,31, 58, 52,35, 59 and 56. 2 In general, however, infection with genital HPV is common in adults, and most infections are cleared by the immune system. The most frequent HPV types isolated in women with normal cytology are, in order of prevalence, HPV 16, 42, 58,31,18, 56, 81,35,33, 45 and 52. 3 Although other factors contribute to the malignant transformation process, it is generally accepted that HPV infection is an absolute requirement. 4,5 Built on the recognition of HPV infection in the etiology of cervical cancer, two commercial vaccines, Gardasil V R and Cervarix V R , have been licensed in 2006 and 2007, respectively. 6,7 Both vaccines are based on the L1 major capsid protein and are highly effective in preventing HPV infection and HPV-induced cervical lesions. 8,9 It is expected that both vaccines will reduce the cervical cancer rate in vaccinated women by 70-80%.Both L1-based vaccines have some limitations including costly production, invasive administration and limited protection against nonvaccine HPV types. The latter is due to the fact that neutralizing anti-L1 binds to surface loops on the viral capsids, which are highly heterogeneous among the dif...

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Hybrid Papillomavirus L1 Molecules Assemble into Virus-like Particles That Reconstitute Conformational Epitopes and Induce Neutralizing Antibodies to Distinct HPV Types

Cited by 112 publications

References 55 publications

Subtype HPV38b[FA125] demonstrates heterogeneity of human papillomavirus type 38

Subtype HPV38b[FA125] demonstrates heterogeneity of human papillomavirus type 38

Replication and Assembly of Human Papillomaviruses

Natural variants in the major neutralizing epitope of human papillomavirus minor capsid protein L2

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