Human papillomaviruses.

Introduction

Papillomaviruses were identified as vital particles in 1949 (108). Although the infectious nature of animal and human warts was well established in the 1890s, no other group of viruses has in recent years undergone such an unprecedented explosive recognition of distinct types and variation in pathogenicity, and as agents of a most important group of human tumorviruses that cause one major human cancer, carcinoma of the cervix.

In 1976 and 1977 the plurality of human papillomavirus (HPV) types became evident (50, 51, 84). Today we recognize 73 genotypes (29, 30), and this number will almost certainly increase in the future. Although, at a superficial glance, such variation suggests a remarkable plasticity and the quick development of mutational adaptations of HPV, the available evidence points in the opposite direction. Specific isolates from nonhuman primates are more closely related to specific human genotypes than the latter are among each other (e.g. pigmy chimp papillomavirus and HPV 13 or rhesus monkey papillomavirus and HPV 16) (see 8). Obviously, the separation of many of the human pathogenic genotypes took place in the early prehominid period; hence, papillomaviruses along with herpesviruses, adenoviruses, and polyomaviruses, and probably others, developed far prior to the emergence of humans. Indeed, these viruses represent fascinating tools for the study of evolutionary aspects of prehominid family trees and early hominid migration patterns (8). Papillomaviruses have also been found in reptiles (turtles), birds, and many other mammals. Therefore, the heterogeneity of this group reflects not so much the fast acquisition of genome modifications, but rather a remarkably ancient history of virus adaptations to specific host cells and host-mediated control of these virus infections.

The major stimulus for the current interest in the papillomavirus group originates from the discovery of their causal relationship to a common form of human cancer, carcinoma of the cervix. This relationship had not been considered prior to 1974 (118, 123), although members of this group were known to be carcinogenic in rabbits (97) and able to malignantly transform certain rodent cells (10). They had also been suspected to play a significant role in a rare skin disease of humans, epidermodysplasia verruciformis (E.V.), which is characterized by a generalized verrucosis with malignant progression of individual warts at sun-exposed sites (64, 66, 75). Slightly less than 10 years later the isolation of specific HPV types directly from biopsies of cancer of the cervix (12, 41) paved the way for detailed studies on their role in the induction of genital cancers. Ten years later, this role appears to be firmly established, confirming after about 150 years the observations made by the Italian physician Rigoni-Stern, published in 1842 in Rome (95). Based on the high prevalence of cancer of the cervix in prostitutes and its virtual absence in nuns, he postulated that a sexually transmitted agent causes this cancer.

Papillomaviruses are unique among human pathogens in permitting studies not only on the role of cell differentiation on virus replication and particle assembly, but on host cell control of potentially oncogenic functions. Such investigations are used to analyze mechanisms of malignant progression, as well as study basic aspects of cellular longevity and senescence. The viruses' intimate relationship to the infected host cell renders them at the same time ideal tools in the analysis of events regulating the cell cycle as well as in the elucidation of the principles governing cell-mediated defense mechanisms against latent virus infections.

Distribution of HPV Infections and Development of Proliferative Lesions

Even HPV types rarely found in the human population are nonetheless widespread globally. The same genotypes from patients with the hereditary condition epidermodysplasia verruciformis (E.V.) occur worldwide at very low frequencies. This syndrome is characterized by an extensive verrucosis and the development of squamous cell carcinomas within papillomas that usually occur at sun-exposed sites (73). It is likely that the genotypes found in this condition, namely HPV types 5, 8, 10, 12, 14, 17, and a few others, are widespread within the human population but fail to cause overt pathogenicity in healthy individuals. Similarly, other HPV types infecting the skin, genitals, or oral mucosa have been discovered in various parts of the world, in line with the suspected ancient relationship of HPV infections and humans.

The mode of transmission is not entirely clear. Infection of basal layer cells in microlesions seems to play a major role. Junctions of different types of epithelia also seem to predispose individuals to these infections, possibly because of the proximity of proliferating cells to the surface of such sites.

Anogenital HPV infections are preferentially transmitted by sexual contact. Although early childhood infections can result from poor hygienic conditions, such infections may also be indicators of sexual abuse (101). Condylomatous lesions in children do, however, frequently contain HPV types regularly found at other cutaneous sites, such as HPV types 2, 27, and 57 (30). Virgins are usually free of detectable anogenital HPV infections (45, 55, 74).

The onset of sexual maturity and activity leads to a high prevalence of anogenital HPV infections in the age groups between 15 and 40 years (31, 78, 112). About 15-35% of this age group contain detectable quantities of HPV DNA and are probably virus shedders (101). Socioeconomic state seems to be related to the prevalence of HPV infections. Presently, estimating the total number of infected individuals in a given population is impossible; sero-epidemiological tests have only recently begun to address this issue, and their value in ascertaining previous infections has not yet been clarified.

In postmenopausal women, the percentage of HPV detectability declines and remains low for the remainder of the life span (31). Currently, we cannot determine whether this reflects a decrease in virus shedding or a clearance of latent infections. Because of the difficulties in obtaining suitable tissue material from men for screening purposes, the vast majority of epidemiological studies have been conducted in women; persistence or latency of these infections in men remains largely unexplored.

Infection of actively proliferating cells by papillomaviruses results in a delay of differentiation and most likely a lateral expansion of the infected clone. This is apparently mediated by functions of the early genes E6, E7, and possibly E5. During the proliferative phase, viral DNA replication and synthesis of viral structural proteins remain restricted. However, this block is released upon entry into the differentiating cell layers, in which DNA replication, structural protein synthesis, and virus particle assembly take place. This mode of infection eventually guarantees that a single cell originally infected by HPV may lead to the emergence of a field of virus-producing cells at the surface of the developing lesion. That these lesions may persist for prolonged periods offers an explanation for the success of HPV's spread throughout the world.

The latter considerations presume a clonal origin of HPV-induced lesions. In a strict sense this was not proven until recently; conflicting evidence had been published in the past (46, 79). The clonal nature of papillomavirus proliferation most likely will depend on the number of proliferating cells exposed to the infection and the infecting dose of the virus. A lesion exposing a larger area of basal layer cells to an HPV infection will result in multiple infected clones, competing with each other in a lateral expansion. This competition suggests polyclonality of the eventually emerging lesion, whereas occasionally exposed basal cells should yield mono- or oligoclonal proliferations.

Obviously, many (probably the majority) HPV infections remain clinically inapparent. They may induce microfoci barely visible with the naked eye, but still contribute to the spread of these infections.

Vital Types, Genome Structure, and Methods of HPV Detection

At present 73 genotypes of HPV have been identified (30). Four additional partially sequenced genotypes, which differ from prototypes, were recently elucidated (E-M de Villiers, unpublished data). A sequence is considered new when the base compositions of specific regions of the vital genome differ by more than 10% (E6, E7, and L1) (30).

Because the majority of HPV types as well as several animal papillomavirus types have been sequenced completely (28), we can determine the closely and distantly related …