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Antiviral Therapy 5:229–242 Review Searching for antiviral drugs for human papillomaviruses Mark R Underwood1, Lisa M Shewchuk2, Anne M Hassell2 and William C Phelps1* 1Department of Virology, GlaxoWellcome, N.C., USA 2Structural Chemistry, GlaxoWellcome, N.C., USA *Corresponding author: Tel: +1 919 483 9242; Fax: +1 919 315 5243; E-mail: [email protected] The human papillomaviruses (HPVs) are ubiquitous cervical carcinoma. The absence of a simple monolayer human pathogens that cause a wide variety of benign cell culture system for analysis and propagation of the and pre-malignant epithelial tumours. Of the almost virus has substantially retarded progress in the devel- 100 different types of HPV that have been characterized opment of diagnostic and therapeutic strategies for to date, approximately two dozen specifically infect HPV infection. In spite of these difficulties, great genital and oral mucosa. Mucosal HPVs are most progress has been made in the elucidation of the mole- frequently sexually transmitted and, with an incidence cular controls of virus gene expression, replication and roughly twice that of herpes simplex virus infection, are pathogenesis. With this knowledge and some important considered one of the most common sexually trans- new tools, there is great potential for the development mitted diseases throughout the world. A subset of of improved diagnostic and prognostic tests, prophy- genital HPVs, termed ‘high-risk’ HPVs, is highly associ- lactic and therapeutic vaccines, and traditional antiviral ated with the development of genital cancers including medicines. A serious and mysterious disease Unlike most sexually transmitted diseases (STDs), or mucosal warts. However, a small proportion of genital human papillomavirus (HPV) infection is not a genital infections with high-risk HPVs result in reportable disease, so precise epidemiological numbers progression to invasive cervical cancer. Although HPV are difficult to obtain [1]. Nonetheless, genital HPV infection is not sufficient for the induction of cancer, infection is clearly one of the most prevalent sexually the causal association between high-risk HPV infection transmitted diseases in the world today. The US Center and cervical cancer is very strong. The odds ratio for for Disease Control has estimated that there are nearly HPV infection (particularly HPV-16) and cervical 5.5 million new cases per year in the USA alone cancer is actually higher than that between cigarette resulting in >20 million active cases [2]. Worldwide, smoking and lung cancer [7,8]. there may be >500 million people infected with genital During the 1930s, cervical cancer was the most HPV. In an alarming study of college-age women, 43% common cause of cancer death in the USA [9]. The PAP converted from HPV-negative to HPV-positive during (Papanicolaou) screen, introduced almost 50 years ago, the 3-year period of study [3], reflective of a very high has become the most effective and frequently used incidence of infection and risk of exposure for students method for the detection of cytopathic effects due to on college campuses. It has been suggested that up to HPV infection of cervical epithelium. Between 80% of sexually active women will acquire an HPV 1947–1984, there was a 70% decline in US mortality infection at some point during their lifetimes [4]. due to cervical cancer, which is directly attributed to Furthermore, the use of condoms does not appear to early detection and ablation of HPV infected, pre- offer protection against the transmission of HPV to malignant tissue [10]. However, the PAP screen is not partners [5]. The financial burden is high; during 1994 commonly used in developing countries, and about the estimated cost of treating HPV infection in the US 200000 deaths per year worldwide are attributed to was $3.8 billion, and the cost for treatment of cervical cervical cancer, ranking it as the second leading cause cancer was $737 million [6]. of cancer death in women behind breast cancer. The majority of HPV infections induce benign, often Despite the prevalence and serious sequelae of HPV self-limiting or transient epithelial lesions – cutaneous infection, HPV remains a mysterious viral disease to ©2000 International Medical Press 1359-6535/00/$17.00 229 MR Underwood et al. most. In a recent survey, 70% of US women were expression of the E6 and E7 viral oncoproteins. These unaware of an aetiological link between virus infection viral genes are known to disrupt two critical cell cycle and cervical cancer, and 76% had never even heard of regulatory pathways featuring the p53 and the HPV (2000 National Cervical Cancer Public Education retinoblastoma proteins (pRB). The deregulation of Campaign). As awareness of HPV-associated disease controls on cellular proliferation and differentiation is increases in the coming years, there is very likely to be thought to directly contribute to the hyperplastic a concomitant rise in pressure for improved diagnostics phenotype characteristic of pre-malignant lesions [17]. and effective therapies. Advances during the past High-risk HPV infection is clearly not sufficient to decade in our understanding of the HPV lifecycle have induce cervical cancer, as only a subset of infected provided important insights into novel therapeutic women will develop cancer, and progression to malig- opportunities. The intent of this review is to focus on nancy requires 10–20 years. These observations potential therapeutic targets for the identification of highlight a potential role for somatic mutations and new antiviral agents that will selectively and effectively suggest that a defining risk factor might be persistence treat HPV disease in the clinic. of high-risk infections [8]. The development of invasive For more detailed descriptions of papillomavirus cervical cancer typically occurs by progression through molecular and cellular biology, as well as immunolog- a series of neoplastic stages characterized by increasing ical and epidemiological aspects of the virus and dysplasia and severity [cervical intraepithelial neoplasia associated diseases, the reader may refer to a number (CIN I–III) or SIL I–II]. Cytological progression is a of other reviews [11–15]. likely sentinel for the accumulation of genetic alter- ations, which endow the tumour cell with various Clinical and therapeutic growth advantages in the local tissue environment. Since HPV-negative cervical carcinomas are relatively Plurality of HPV types rare (<5%), it is commonly believed that the continued More than 80 HPV types have been characterized to presence and expression of the viral genome is critical date, based on nucleotide sequence comparison with to maintenance of the dysplastic or malignant pheno- around another 100 that have been only partially char- type. Additional risk factors for progression to cancer acterized [13]. A discrete HPV type is defined as having may include a genetic predisposition of the host. Studies less than 90% nucleotide sequence homology within to characterize host genetic influences on HPV infec- the L1 region of all other known types. The biological tion, clearance and disease progression are currently at and genetic factors that are responsible for the remark- an early stage, although they may be substantially accel- able plurality of HPVs are not well understood. HPV erated as the human genome sequence is completed. infection is strictly epitheliotropic, and different HPV types are commonly categorized according to their Low-risk infection tissue specificity as either mucosal or cutaneous HPVs. The most familiar and commonly encountered HPV infection in the population results in the growth of High-risk infection benign cutaneous warts. Infection is very common, Approximately 30 types of HPV have been found to although cutaneous warts are somewhat more preva- infect mucosal epithelium, with most genital infections lent in children than in adults. It has been estimated being associated with HPV types 6, 11, 16, 18, 31, 33 that 7–10% of the population has benign cutaneous and 45. HPV types are commonly divided into two warts [18]. Common, plantar and palmar warts are groups, ‘low-risk’ and ‘high-risk’, based upon their typically caused by HPV types 1, 2, 3, 4 and 10 [12], relative association with malignant progression. and are thought to be transmitted by person-to-person Infection of the genital mucosa by HPV types 6 and 11 contact with infected tissue. Though strictly benign causes genital warts that are considered benign and and primarily a cosmetic nuisance, cutaneous warts ‘low-risk’ because of a poor association with progres- can be painful and may persist for years before spon- sion to invasive cancer. In contrast, high-risk HPV taneous regression occurs. types, HPV-16, -18, -31, -33 and -45, are highly asso- Benign genital warts, or condyloma acuminata, are ciated with persistent and progressive squamous typically caused by infection of the genital mucosa with intra-epithelial lesions (SIL) and with a relatively high- HPV types 6 and 11. Genital warts is a STD and, with risk for the development of cervical cancer. High-risk an estimated incidence of 1–3 million new cases per HPV types have been associated with 80–98% of cases year in the USA alone, it ranks as one of the most of invasive cervical cancer [16]. In addition to the prevalent STDs in the world today [1]. Papillary genital strong epidemiological association, high-risk HPV- warts often grow in clusters and can be readily DNA is frequently found to be integrated into