Development and characterization of a novel xenograft model permissive for human papillomavirus DNA amplification and late gene expression

Sexton, Connie J.; Williams, Anthony T.; Topley, Peter; Shaw, R. J.; Lovegrove, Carol; Leigh, Irene M.; Stables, Jeremy N.

doi:10.1099/0022-1317-76-12-3107

Cited by 11 publications

(10 citation statements)

References 8 publications

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“…Because of this dependence, it was difficult to efficiently generate PVs in vitro and the study of PV infection had been hindered until 1990s. Organotypic raft cultures and mouse xenografts were the first methods that were used to generate PVs [10–13]. These methods were technically demanding and produced relatively low yields of virions.…”

Section: Introductionmentioning

confidence: 99%

HPV entry into cells

Aksoy

Gottschalk

Meneses

2017

Mutation Research/Reviews in Mutation Research

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Human papillomavirus (HPV) is a sexually transmitted virus responsible for the development of cervical cancer, anal cancer, head and throat cancers, as well as genital area warts. A major focus of current HPV research is on preventing the virus from entering a cell and transferring its genetic material to the nucleus, thus potentially preventing the development of cancer. Although the available HPV vaccines are extremely successful, approximately 15 additional cancer-causing HPVs have been identified that the vaccines do not protect against. Therefore, roughly 150,000 cancer cases will not be prevented annually with the current vaccines. Research efforts focused on the basic cell biology of HPV infection have a goal of identifying common infectious events that may lead to inexpensive vaccines or anti-virals to prevent infection by most, if not all, HPVs. In this review we attempt to summarize what is known regarding the process of HPV binding, entry, and intracellular trafficking.

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Section: Introductionmentioning

confidence: 99%

HPV entry into cells

Aksoy

Gottschalk

Meneses

2017

Mutation Research/Reviews in Mutation Research

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“…The requirement for terminal differentiation of epithelial cells to support the productive stage of the viral life cycle precludes obtaining infectious virus particles from conventional cell culture. Consequently, the only prior methods capable of producing infectious papillomavirus virions were organotypic raft culture (12)(13)(14)(15), by which small quantities of artificial skin can be produced in cell culture, or the use of xenografts in mouse skin (16)(17)(18). However, these methods are technically demanding, time-consuming, and variable, and they produce relatively low virus yields and require access to epithelial cell populations or human tissue in which the viral genotype of interest persists as a nuclear plasmid.…”

mentioning

confidence: 99%

Production of infectious human papillomavirus independently of viral replication and epithelial cell differentiation

Pyeon

Lambert

Ahlquist

2005

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

108

137

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Papillomaviruses are small DNA viruses that are associated with benign and malignant epithelial lesions, including >95% of cervical cancers and Ϸ20% of head and neck cancers. Because papillomavirus replication and virion production are tied to epithelial cell differentiation, infectious papillomavirus virion production has been limited to cumbersome organotypic cultures and mouse xenografts. Consequent difficulties in obtaining useful amounts of wild-type or mutant human papillomavirus (HPV) virions have greatly limited studies on many aspects of papillomavirus biology. To overcome these limitations, we developed a system to encapsidate the full-length papillomaviral genome into infectious virions, independently of viral DNA replication and epithelial differentiation. This transient-transfection-based system produces >1,000 times more infectious virus per cell culture dish than the much more labor-intensive organotypic culture. Furthermore, we show that this method allows the facile generation of infectious particles containing wild-type, mutant, or chimeric papillomaviral genomes, overcoming barriers to studying many facets of replication, host interactions, and vaccine and drug development, which has been limited by the insufficient availability of infectious virions.infection ͉ virions ͉ virus packaging ͉ capsid ͉ DNA encapsidation P apillomaviruses are nonenveloped, double-stranded DNA viruses with Ϸ8-kb, circular genomes, 55-nm spherical capsids, wide distribution in higher vertebrates, and tight species specificity (1). Human papillomaviruses (HPVs), of which there are Ͼ100 genotypes, infect and replicate in cutaneous or mucosal epithelia, inducing benign lesions, including warts that are self-limiting and normally regress over time (2, 3). A subset of mucosotropic HPVs, the high-risk genotypes, such as HPV16, HPV18, and HPV31, are causally associated with anogenital cancers, including nearly all, if not all, cervical carcinomas, a leading cause of cancer death among women worldwide (1, 4, 5). Also, high-risk HPVs (in particular, HPV16) are associated with 20-30% of head and neck cancers (6, 7), the sixth most common cancer in the United States, of which the survival rate is Ͻ50% and has not improved for decades (8).The HPV life cycle is tightly linked to epithelial differentiation (9, 10). HPVs initially infect cells of the poorly differentiated, proliferative, basal compartment of stratified epithelia. Here, the viral genome sets up residence as a low-copy nuclear plasmid, a subset of viral genes (the early genes) are expressed at low levels, and no progeny virus is made. However, as infected basal cells divide and daughter cells migrate into the suprabasal compartment for terminal differentiation, the productive stage of the viral life cycle is initiated (10, 11). Here, the virus reprograms suprabasal cells to support high-copy-number amplification of the viral genome, the viral structural genes encoding the major L1 and minor L2 capsid proteins are expressed, and progeny virions are assembled and then ...

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“…Overexpression of the oncogenes from human papilloma virus type 16, E6 and E7 had no morphogenetic consequences because dermal ¢broblasts in contrast to keratinocytes and melanocytes are nonpermissive for the tumorigenic activity of these oncogenes (Brandsma et al, 1995;Sexton et al, 1995). This suggested that induced expression of the gene has to occur in the appropriate tissue compartment.…”

Section: Discussionmentioning

confidence: 99%

Stroma Formation and Angiogenesis by Overexpression of Growth Factors, Cytokines, and Proteolytic Enzymes in Human Skin Grafted to SCID Mice

Gruss

Satyamoorthy

Berking

et al. 2003

Journal of Investigative Dermatology

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Reorganization of skin during wound healing, inflammatory disorders, or cancer growth is the result of expression changes of multiple genes associated with tissue morphogenesis. We wanted to identify proteins involved in skin remodeling and select those that may be targeted for agonistic or antagonist therapeutic approaches in various disease processes. Full-thickness human skin was grafted to severe combined immunodeficient mice and injected intradermally with 38 different adenoviral vectors inserted with 37 different genes coding for growth factors, cytokines, proteolytic enzymes and their inhibitors, adhesion receptors, oncogenes, and tumor suppressor genes. Responses were characterized for infiltration of inflammatory cells, vascular density, matrix formation, fibroblast-like cell proliferation, and epidermal hyperplasia. Of the 17 growth factor vectors, 16 induced histological changes in human skin. Members of the VEGF and angiopoietin families induced neovascularization. PDGFs and TGF-betas stimulated connective tissue formation, and the chemokines IL-8 and MCP-1 attracted inflammatory neutrophils and monocytes, respectively. The serine protease uPA induced a vascular response similar to that of VEGF. Vectors with adhesion receptors, oncogenes and tumor suppressor genes had, with few exceptions, little effects on skin architecture. The overall results suggest that adenoviral vectors can effectively remodel the architecture of human skin for studies in morphogenesis, inflammatory skin disorders, wound healing, and cancer development.

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Development and characterization of a novel xenograft model permissive for human papillomavirus DNA amplification and late gene expression

Cited by 11 publications

References 8 publications

HPV entry into cells

HPV entry into cells

Production of infectious human papillomavirus independently of viral replication and epithelial cell differentiation

Stroma Formation and Angiogenesis by Overexpression of Growth Factors, Cytokines, and Proteolytic Enzymes in Human Skin Grafted to SCID Mice

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