Human papillomavirus vaccines

Breitburd, Françoise; Coursaget, Pierre

doi:10.1006/scbi.1999.0147

Cited by 72 publications

(48 citation statements)

References 79 publications

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“…Anti-HVR1 antibodies specific for one variant display only a limited ability to neutralize different viral variants (17,18). The efficacy of a vaccine based on structural proteins could be impaired if escape mutants were present (6,25,30,38,53,58).…”

Section: Discussionmentioning

confidence: 99%

Molecular Epidemiology of Hepatitis C Virus Genotype 4 Isolates in Egypt and Analysis of the Variability of Envelope Proteins E1 and E2 in Patients with Chronic Hepatitis

et al. 2005

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We analyzed hepatitis C virus (HCV) genotype 4 isolates circulating in the Alexandria District (Egypt) in terms of genetic divergence and the presence of different subtypes. Hypervariable region 1 (HVR1) and the NH2 region of the E2 protein were characterized, and the heterogeneity of subtype 4a isolates was evaluated by analyzing epitope frequencies, immunoproteasome prediction, and possible glycosylation patterns. The heterogeneity of the nucleotide sequences was greater than that found in previous studies, which reported only subtype 4a. Subtype 4a was most common (78% of cases), yet four new subtypes were found, with subtype 4m representing 11% of the cases and the other three subtypes representing another 11%. Substantial heterogeneity was also found when the intrasubtype 4a sequences were analyzed. Differences in the probability of glycosylation and in the positions of the different sites were also observed. The analysis of the predicted cytotoxic-T-lymphocyte epitopes showed differences in both the potential proteosome cleavage and the prediction score. The Egyptian isolates in our study also showed high variability in terms of the HVR1 neutralization epitope. Five of these isolates showed amino acid substitutions never previously observed (a total of six positions). Four of these residues (in four different isolates) were in positions involved in anchoring to the E2 glycoprotein core and in maintaining the HVR1 conformation. The results of this study indicate that HCV genotype 4 in Egypt is extremely variable, not only in terms of sequence, but also in terms of functional and immunological determinants. These data should be taken into account in planning the development of vaccine trials in Egypt.Hepatitis C virus (HCV) is the major etiological agent of chronic hepatitis and liver disease worldwide, and it is a major cause of morbidity and mortality. In 80% of cases, infection with HCV results in chronic hepatitis, possibly leading to cirrhosis and hepatocellular carcinoma (11,28).HCV is characterized by a high degree of nucleotide sequence variability. Overall, the heterogeneity of the viral genome ranges from 30 to 35% between different genotypes, although it varies with the specific region of the genome, and it has been used to define three types of regions: highly conserved regions (e.g., the 5Ј untranslated region), variable regions (e.g., envelope 1 [E1] and nonstructural 5b [NS5b]), and hypervariable regions (HVR) (e.g., HVR1 and HVR2 in E2) (48). Furthermore, because of errors of the RNA-dependent RNA polymerase, HCV has a high rate of mutation during replication, and it exists in the bloodstreams of infected persons as complex distributions of mutants known as viral quasispecies, which fluctuate during the course of the disease, mainly as a result of immune pressure (47,51,54). These coexisting mutant genomes always have a consensus, or master, sequence. In general, despite the potentially high mutation rate and variability of RNA viruses, changes in the consensus sequence of a viral population ...

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Section: Discussionmentioning

confidence: 99%

Molecular Epidemiology of Hepatitis C Virus Genotype 4 Isolates in Egypt and Analysis of the Variability of Envelope Proteins E1 and E2 in Patients with Chronic Hepatitis

et al. 2005

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“…An effective vaccine against HPV infection would potentially prevent the development of most human cervical dysplasias and carcinomas (4). In addition, a vaccine would also reduce the cost (estimated at $6 billion annually in the United States) of screening and treating premalignant cervical disease (16).…”

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confidence: 99%

Immunization with a Pentameric L1 Fusion Protein Protects against Papillomavirus Infection

Yuan

Estes

Chen

et al. 2001

J Virol

124

105

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The prophylactic papillomavirus vaccines currently in clinical trials are composed of viral L1 capsid protein that is synthesized in eukaryotic expression systems and purified in the form of virus-like particles (VLPs). To evaluate whether VLPs are necessary for effective vaccination, we expressed the L1 protein as a glutathione S-transferase (GST) fusion protein in Escherichia coli and assayed its immunogenic activity in an established canine oral papillomavirus (COPV) model that previously validated the efficacy of VLP vaccines. The GST-COPV L1 fusion protein formed pentamers, but these capsomere-like structures did not assemble into VLPs. Despite the lack of VLP formation, the GST-COPV L1 protein retained its native conformation as determined by reactivity with conformation-specific anti-COPV antibodies. Most importantly, the GST-COPV L1 pentamers completely protected dogs from high-dose viral infection of their oral mucosa. L1 fusion proteins expressed in bacteria represent an economical alternative to VLPs as a human papillomavirus vaccine.Genital human papillomavirus (HPV) infection is a common sexually transmitted disease that is the primary cause of cervical cancer, resulting in approximately 400,000 deaths per year worldwide (30). An effective vaccine against HPV infection would potentially prevent the development of most human cervical dysplasias and carcinomas (4). In addition, a vaccine would also reduce the cost (estimated at $6 billion annually in the United States) of screening and treating premalignant cervical disease (16).Since HPV cannot replicate in other animal species, evaluation of potential HPV vaccines requires the use of related animal papillomaviruses. The mucosotropic, oncogenic canine oral papillomavirus (COPV) closely mimics the biology of HPV, and the capsid proteins of COPV are closely related to those of HPV, making COPV a relevant and accepted animal model for testing the efficacy of prophylactic vaccine candidates (2,19,26,27).The L1 capsid protein of papillomaviruses self-assembles into virus-like particles (VLPs) when expressed in insect cells (11,14) or yeast (12,23). These L1 VLPs are morphologically similar to virions, being comprised of 72 pentamers (i.e., capsomeres) of L1 arranged in a Tϭ7 icosahedral lattice, but lacking the L2 capsid protein and the viral genome. Previous studies have shown that immunization with purified VLPs protects against experimental papillomavirus infection in rabbits (5, 8), cows (15), and dogs (27). Conformational epitopes on VLPs appear critical for the induction of neutralizing immunoglobulin G (IgG) and for successful vaccination, since denatured L1 protein fails to generate neutralizing antibodies or protect against experimental infection (10,18,27).Although early attempts to use bacteria for producing papillomavirus L1 protein vaccines were unsuccessful due to poor immunogenicity or inefficient expression (1, 9, 13, 28, 29), recent studies have shown that the HPV type 11 (HPV-11) and HPV-16 L1 proteins can be expressed in Escherichia col...

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“…Furthermore, continuous expression of E6 and E7 oncoproteins is necessary for the maintenance of the transformed phenotype. These properties have made E6 and E7 targets of various experimental therapeutics, including vaccination-, antisense RNA-, and ribozyme-based approaches (4,11,41).…”

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confidence: 99%

Human Papillomavirus E6E7-Mediated Adenovirus Cell Killing: Selectivity of Mutant Adenovirus Replication in Organotypic Cultures of Human Keratinocytes

Balagué

Noya

Alemany

et al. 2001

J Virol

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Replication-competent adenoviruses are being investigated as potential anticancer agents. Exclusive virus replication in cancer cells has been proposed as a safety trait to be considered in the design of oncolytic adenoviruses. From this perspective, we have investigated several adenovirus mutants for their potential to conditionally replicate and promote the killing of cells expressing human papillomavirus (HPV) E6 and E7 oncoproteins, which are present in a high percentage of anogenital cancers. For this purpose, we have employed an organotypic model of human stratified squamous epithelium derived from primary keratinocytes that have been engineered to express HPV-18 oncoproteins stably. We show that, whereas wild-type adenovirus promotes a widespread cytopathic effect in all infected cells, E1A-and E1A/E1B-deleted adenoviruses cause no deleterious effect regardless of the coexpression of HPV18 E6E7. An adenovirus deleted in the CR2 domain of E1A, necessary for binding to the pRB family of pocket proteins, shows no selectivity of replication as it efficiently kills all normal and E6E7-expressing keratinocytes. Finally, an adenovirus mutant deleted in the CR1 and CR2 domains of E1A exhibits preferential replication and cell killing in HPV E6E7-expressing cultures. We conclude that the organotypic keratinocyte culture represents a distinct model to evaluate adenovirus selectivity and that, based on this model, further modifications of the adenovirus genome are required to restrict adenovirus replication to tumor cells.Among human cancers, one of the most distinctive features of anogenital carcinomas is its virological nature. Numerous reports have established the causal association of human papillomavirus (HPV) infections with squamous carcinomas and adenocarcinomas of the anogenital tract (9, 49). Over 95% of cervical tumors contain integrated HPV sequences that belong to the oncogenic HPV group (HPV16, -18, and related types) (49) and consistently express papillomavirus early 6 and 7 oncogenes (38, 42). E6 and E7 oncoproteins interact with the master cell cycle regulatory proteins, p53 and pRB, respectively (17, 36), and are able to immortalize primary keratinocytes in vitro and cause cell transformation in cooperation with other oncoproteins, such as activated Ras (34, 37, 44). Furthermore, continuous expression of E6 and E7 oncoproteins is necessary for the maintenance of the transformed phenotype. These properties have made E6 and E7 targets of various experimental therapeutics, including vaccination-, antisense RNA-, and ribozyme-based approaches (4, 11, 41).Although a virus-based therapeutic approach for the treatment of cancer is not a novel concept, recent years have witnessed with increasing attention the design of new oncolytic adenoviruses (for a review, see reference 1). Since the discovery of adenovirus in 1953, the knowledge about adenovirus biology and the interaction with its hosts has helped identify the need to introduce safety traits, such as the restriction of adenovirus replication to tumor...

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Human papillomavirus vaccines

Cited by 72 publications

References 79 publications

Molecular Epidemiology of Hepatitis C Virus Genotype 4 Isolates in Egypt and Analysis of the Variability of Envelope Proteins E1 and E2 in Patients with Chronic Hepatitis

Molecular Epidemiology of Hepatitis C Virus Genotype 4 Isolates in Egypt and Analysis of the Variability of Envelope Proteins E1 and E2 in Patients with Chronic Hepatitis

Immunization with a Pentameric L1 Fusion Protein Protects against Papillomavirus Infection

Human Papillomavirus E6E7-Mediated Adenovirus Cell Killing: Selectivity of Mutant Adenovirus Replication in Organotypic Cultures of Human Keratinocytes

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