Antiviral Therapy for Human Papillomaviruses: Rationale and Prospects

It is not generally appreciated that the human papillomaviruses (HPVs) are the most common sexually transmitted viral agents in the United States, infecting as many as 5% to 20% of persons aged 15 to 49 years [1]. Because genital HPV infection is not a reportable disease, accurate epidemiologic data are not readily available; however, the Centers for Disease Control and Prevention has estimated that nearly 1 million new cases of genital warts are diagnosed every year in the United States alone [2]. As with other sexually transmitted diseases, HPV infection often occurs in association with diseases such as syphilis, gonorrhea, chlamydia, herpes simplex virus (HSV), and human immunodeficiency virus (HIV). Human papillomavirus infection is common across all races and socioeconomic groups and is prevalent throughout the world in sexually active persons. In the last 30 years, the incidence of genital HPV infection has increased dramatically. It has been estimated that the number of physician visits in the United States for genital warts increased from fewer than 200 000 in 1966 to 1.15 million in 1984 [3, 4]. This incidence has continued to increase throughout the latter part of the 1980s, with almost 1.5 million consultations annually [5]. The dramatic increase in the number of patients seeking diagnosis and therapy for HPV infection may be partly due to an increased awareness and recognition by both the public and clinicians. The highest prevalence of genital HPV infection is found in sexually active women younger than age 25 years. Polymerase chain reaction analysis of genital specimens from women attending university infirmaries indicated that as many as 40% had some evidence of HPV infection [6]. A hybridization analysis for viral DNA found that 15% of adolescent females attending family planning clinics had evidence of an HPV infection and that 76% of the HPV-positive females had a normal Papanicolaou smear result [7]. A separate comparative analysis of 454 women attending a sexually transmitted diseases clinic and 545 college women showed that 11% of the patients with a sexually transmitted disease but only 2% of the college students presented with visible genital warts. In this study, however, analysis of cervical specimens from women without visible lesions showed that 10% of the patients with a sexually transmitted disease and 11% of the students were positive for HPV DNA or antigen [8]. Although the prevalence of asymptomatic or clinically inapparent disease is uncertain, clearly a substantial proportion of infected persons progress to condylomata or to cervicovaginal dysplasia and cervical cancer. The greatest prevalence of high-grade cervical dysplasia is found in women older than age 25 years, with the peak incidence of cervical cancer occurring after age 35 years [9]. Because most cases of cervical dysplasia and carcinoma (approximately 90%) are associated with HPV infection, the increasing prevalence of genital warts in young women may portend a future epidemic increase in the rate of premalignant disease and cervical cancer. Despite the high prevalence of HPV infection, no available drug therapy effectively eliminates HPV infection and replication or prevents HPV-associated malignant progression. As a consequence, there is a striking unmet medical need for the development of safe and effective therapies for HPV-associated disease. Current treatment relies on excision or ablation of dysplastic or malignant tissue and is associated with substantial rates of recurrence, discomfort, and expense [10, 11]. Although papillomaviruses cannot yet be routinely cultured in the laboratory, the tools of molecular virology have been used extensively in the last 10 years to study the functions of the 8 to 10 individual viral genes. Several of the viral gene products represent attractive targets for the development of antiviral inhibitors. We examine the current state of antiviral investigations and the prospects for the development of potent and clinically useful therapies for inhibiting HPV replication and pathology. General Properties of the Human Papillomaviruses The papillomaviruses are members of the Papovaviridae family and infect most vertebrate species with exclusive host and tissue specificity. The virion is a small, nonenveloped icosahedral capsid that contains a single molecule of supercoiled, double-stranded, circular DNA about 8000 base-pairs in length. Viral DNA is replicated in the nuclei of infected cells in association with low-molecular-weight histones and is organized into nucleosomal structures that are reminiscent of host cellular chromatin. The genomes of many of the animal and human papillomaviruses have been completely sequenced. The arrangement of the open-reading frames, which are translated into viral proteins, and the nucleotide and amino-acid sequences of certain domains of the viral proteins have been well conserved during evolution of the animal and human viruses. As shown in Figure 1, the viral genome can be bisected into early (E1 to E7) and late regions (L1 and L2) separated by a 1-kb long control region (LCR), which contains transcriptional control elements and the origin of viral DNA replication. By convention established for other DNA viruses, viral genes designated as early encode functions that are important for the establishment of infection and for the initiation of viral DNA replication. The late genes encode the viral capsid proteins, the expression of which is normally delayed until after viral DNA is amplified [12]. Figure 1. A circular map of the double-stranded genome of human papillomavirus type 11 (HPV-11) (229). For many years, it was assumed that all infectious human epidermal lesions were caused by a single human wart virus. It was not until the mid-1970s that restriction-endonuclease mapping and hybridization analysis provided the earliest indication of the remarkable plurality of HPV genotypes. Approximately 70 different HPV types are currently recognized and have been isolated from various mucosal and cutaneous epithelial lesions (Table 1). Human papillomaviruses are normally grouped according to their pathologic associations and tissue specificity as cutaneous or mucosal [13]. The 23 mucosal-associated HPVs can be further subdivided into those at high risk for malignant progression and those at low risk for progression [14]. Table 1. Human Papillomaviruses Associated with Human Disease Nonmalignant Human Papillomavirus Disease Cutaneous Warts The most common and familiar result of HPV infection is the development of a localized, benign epithelial neoplasm or wart. Cutaneous palmar and plantar warts are widespread in the population and are typically found to contain HPV types 1, 2, 3, 4, or 10. Cutaneous warts can persist or grow slowly for years and then abruptly disappear without apparent cause or therapy. The incidence of benign warts is highest in children and young adults and decreases later in life, presumably because of the development of systemic immunity. Plantar and palmar warts are considered to be exclusively benign. Considering the ubiquity of common skin warts in humans and the relation of other types of HPV to cancer, it is remarkable that the reported incidence of malignant conversion of skin warts is essentially 0. In addition, the sites of infection, commonly the hands and feet, are frequently exposed to mechanical trauma or other potential cocarcinogenic factorshumans are often in contact with the environment through bare hands and feet. These observations show and support a seminal theme in the pathobiology of HPV disease: The potential for malignant conversion of HPV-associated lesions is, at least in part, determined by the infecting HPV genotype and its target tissue. Condyloma Acuminata In the United States, the incidence of HPV-associated genital warts is increasing dramatically. Ranking only behind chlamydial infection and gonorrhea, sexually transmitted genital warts are one of the fastest growing sexually transmitted diseases in the United States, with an estimated incidence two to three times that of genital herpes. Clusters of exophytic condylomata generally develop on the penis, vagina, vulva, and perineum and around the anus. Only rarely do condylomata develop on the cervix. More than 90% of the lesions examined are associated with infection by the low-risk HPV types 6 and 11, the same two virus types associated with respiratory papillomatosis [15-17]. Condylomata may spontaneously regress or persist for years. Progression to invasive carcinoma is seen at a relatively low frequency [14]. During pregnancy, condylomata have been observed to increase in both size and number, possibly because of the stimulatory effect of steroid hormones on HPV transcription [18, 19] or because of a decrease in host-cell-mediated immunity. Benign condylomata are often resistant to various forms of therapy, which results in high recurrence rates (30% to 90%). In addition to the social stigma associated with them, genital warts can be painful, may spread locally in an individual patient, and are infectious to sexual partners. Approximately two thirds of the sexual partners of patients with condylomata have been observed to develop genital warts during a 1- to 8-month observation period [5]. Although condylomata are not generally considered life-threatening, without effective antiviral therapy they represent a substantial problem in therapeutic and epidemiologic management. Laryngeal Papillomas Laryngeal or recurrent respiratory papillomas are benign epithelial tumors that usually develop on the larynx and are associated with infection by HPV types 6 and 11 [20, 21]. Although spontaneous malignant conversion is rare [22], therapeutic irradiation of juvenile laryngeal papillomas has been associated with a high incidence of carcinoma 5 to 40 years after treatment [23]. More recently, HPVs have been identified in lesions of the nose and oral cavity and h