Papillomavirus Life Cycle Organization and Biomarker Selection

Disease Markers, Jul 2018

Human papillomaviruses (HPVs) are a diverse group of viruses that cause epithelial lesions of varying severity. Of the 100 or so types that have been identified, around 40 can infect the cervix, with a subset of these causing lesions that can progress to high-grade neoplasia and cervical cancer. These high-risk types are prevalent in the general population, and can predispose to the development of cancer in women who cannot resolve their infection. Virus infection usually leads to the establishment of productive flat warts, or to maintenance of the viral genome in an asymptomatic or latent state. Virus synthesis depends on the ordered expression of viral gene products as the infected basal cell migrates towards the epithelial surface. E7 is expressed in the lower epithelial layers, and is followed eventually by the expression of E4 and L1 closer to the epithelial surface. This ordered pattern changes in characteristic ways during neoplastic progression and latency, and can be irreversibly fixed following integration of the viral genome into the host cell chromosome. Our understanding of expression patterns and their significance, is beginning to explain the nature of disease progression, and offers a rational basis for the selection of biomarkers that may be used to predict disease status and prognostic outcome.

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Papillomavirus Life Cycle Organization and Biomarker Selection

Disease Markers 0278-0240 Papillomavirus life cycle organization and biomarker selection John Doorbar 0 0 National Institute for Medical Research , The Ridgeway, Mill Hill, London, NW7 1AA , UK Tel.: Human papillomaviruses (HPVs) are a diverse group of viruses that cause epithelial lesions of varying severity. Of the 100 or so types that have been identified, around 40 can infect the cervix, with a subset of these causing lesions that can progress to high-grade neoplasia and cervical cancer. These high-risk types are prevalent in the general population, and can predispose to the development of cancer in women who cannot resolve their infection. Virus infection usually leads to the establishment of productive flat warts, or to maintenance of the viral genome in an asymptomatic or latent state. Virus synthesis depends on the ordered expression of viral gene products as the infected basal cell migrates towards the epithelial surface. E7 is expressed in the lower epithelial layers, and is followed eventually by the expression of E4 and L1 closer to the epithelial surface. This ordered pattern changes in characteristic ways during neoplastic progression and latency, and can be irreversibly fixed following integration of the viral genome into the host cell chromosome. Our understanding of expression patterns and their significance, is beginning to explain the nature of disease progression, and offers a rational basis for the selection of biomarkers that may be used to predict disease status and prognostic outcome. - Human papillomaviruses (HPV) complete their productive cycle in stratified epithelial tissue such as cutaneous skin or mucosal epithelium. They can infect many epithelial sites and cause a wide variety of epithelial lesions, including common warts, verrucas, laryngeal papillomas, and genital condyloma. The different types of epithelial lesion, are in general, caused by different groups or types of HPV, with some types showing a very restricted tissue tropism [ 6,34 ]. This is the case with viruses such as HPV1, which causes cutaneous lesions at palmar and plantar surfaces (Fig. 1A). DNA sequence analysis over the last 25 years has shown that papillomaviruses are a very diverse group with over 100 human members [ 34 ]. Most HPV types belong to the Alpha or Beta genus, with the two groups having quite distinct biology and life cycle patterns. The Alpha papillomaviruses are found only in humans and primates, and it is this group that contains the HPV types that are frequently associated with cervical cancer. HPV16 (α9) causes over 50% of all cervical cancers, while HPV18 (α7) is responsible for around 20% of cases (Fig. 1B). These HPV types are classified as high-risk, and are amongst 20 or so such viruses that infect the cervix (Fig. 1B). The Alpha papillomaviruses also contain low-risk members that infect the cervix, but these are not generally associated with cervical cancer. HPV types such as HPV6 and HPV11 (α10) are the best studied of these, and are also responsible for the production of external genital warts that can be a problem in young adults. Although not generally life threatening, such lesions can be difficult to treat effectively in some patients [ 94 ]. The Alpha papillomavirus genus also contains cutaneous HPV types such as HPV2 (α4), which is a prominent cause of common warts in children. The different biology of Alpha papillomavirus members (high-risk, low-risk and cutaneous) is clearly reflected at the level of virus evolution, when whole genomic sequences are compared (Fig. 1B). Beta papillomaviruses are evolutionarily distinct from the Alpha genus (Fig. 1A), and appear to cause widespread in-apparent or asymptomatic infections in the general population, with children becoming infected at an early age. In immunosuppressed patients, and in individuals suffering from the inherited disease Epidermodysplasia Verruciformis (EV), these viruses can spread unchecked, and have been implicated in the development of non-melanoma skin cancer cancer [ 55,96 ]. EV patients carry mutations in their EVER1/TMC6 or EVER2/TMC8 genes, which renders them particularly susceptible to these viruses [ 97,112 ]. The remaining HPV types come from the Gamma, Mu and Nu genus, and cause visible cutaneous papillomas that do not generally progress to cancer (Fig. 1A). Only two Mu HPV types are known (HPV1 and 63), and the Nu Genus comprises only one member. 2. Similarities in the organization of all papillomavirus genomes All papillomaviruses consist of a double stranded circular genome of around 8kb containing one coding strand, encapsidated in an icosohedral protein shell made up of a major (L1) and minor (L2) coat protein (Fig. 2A). 360 molecules of L1 and approximately 12 molecules of L2 are needed for the formation of an infectious virion [ 76 ]. The L1 and L2 proteins are conserved across widely divergent papillomaviruses, and along with E1 and E2, are key viral gene products that are thou (...truncated)


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John Doorbar. Papillomavirus Life Cycle Organization and Biomarker Selection, Disease Markers, 23, DOI: 10.1155/2007/613150