Chapter 66Papovaviruses

Butel JS.

General Concepts

Polyomavirus

Clinical Manifestations

Polyomaviruses exhibit asymptomatic persistent infections in humans. They induce tumors in laboratory rodents. The JC type of polyomavirus causes progressive multifocal leukoencephalopathy in humans.

Structure

Polyomaviruses are icosahedral, 45-nm diameter particles, with three capsid proteins and no envelope. They contain a 5-kbp circular, double-stranded DNA genome. The genome structure is similar for all members of the polyomavirus group and consists of two or three replicative genes (tumor antigens) encoded on one strand and three structural genes (capsid antigens) encoded on the other strand.

Classification and Antigenic Types

Classification is based on the structure of the viral particle. Human and animal polyomaviruses are antigenically distinct; only one serotype is known for each virus. The prototype is simian virus 40 (SV40) from monkeys.

Multiplication

Viral DNA uncoats in the nuclei of infected cells. Early viral genes are expressed and host cells are stimulated to enter the S phase, providing cellular enzymes that are utilized for viral DNA synthesis. Late viral genes are expressed, and progeny virions are assembled in nuclei. Cell lysis occurs later. Viral particles usually stay associated with cell debris. The papovaviruses have oncogenic potential (the papillomaviruses in their natural hosts and the polyomaviruses under experimental conditions).

Pathogenesis

Human polyomaviruses establish persistent infections in the kidneys; these infections may reactivate in immunosuppressed hosts and during some normal pregnancies. Progressive multifocal leukoencephalopathy is a rare demyelinating disease of the central nervous system of some immunosuppressed patients. It is caused by replication of JC virus in oligodendrocytes. Although oncogenic in rodents, polyomaviruses are not believed to be important factors in human cancers.

Host Defenses

Infections are persistent and induce production of humoral antibodies and cytotoxic T cells. Viral reactivation occurs in immunosuppressed persons. Impaired cell-mediated immunity is the background for the development of progressive multifocal leukoencephalopathy. Interferon is weakly induced by papovaviruses, which vary in their sensitivity to the antiviral action of interferon. Transformation by polyomaviruses can be inhibited by interferon.

Epidemiology

BK and JC types of polyomavirus are widespread. Infections occur during childhood, and 70 to 80 percent of adults have antibodies. The route of transmission is unknown, but may be respiratory. Human viruses have no animal reservoirs. A small percentage of humans also possess antibodies to SV40, a simian virus. The mechanism of exposure to SV40 is unknown.

Diagnosis

Clinical presentation and the presence of antibodies are the best means of diagnosis.

Control

There are no known control measures.

Papillomavirus

Clinical Manifestations

Clinical manifestations include benign papillomatous lesions of skin and mucous membranes (common warts, plantar warts, flat warts, anogenital warts, epidermodysplasia verruciformis, and laryngeal papillomas). Cervical intraepithelial neoplasia and cervical cancer are associated with human papillomavirus infection.

Structure

Papillomaviruses are similar to polyomaviruses, except that the particles are 55 nm in diameter, the DNA is 8 kbp in size, and the genome structure is more complex. All viral genes are encoded on one strand of DNA.

Classification and Antigenic Types

Classification is based on the structure of the viral particle. Reagents are not available for serotyping; human papillomavirus types are distinguished by DNA hybridization assays or DNA sequence analysis. There are more than 70 human types.

Multiplication

Replication is dependent on the differentiated state of epithelial cells. Viral DNA remains latent (not integrated) in basal cells of benign lesions. Replication occurs in differentiating cells. Capsid proteins and viral particles are found only in terminally differentiated epidermal cells. Viral DNA is integrated in cancer cells, which contain no replicating virus.

Pathogenesis

Different human papillomavirus types cause specific lesions. The pathogenic mechanisms are not well understood. A few specific types, notably human papillomavirus types 16 and 18, are associated with the development of premalignant and malignant genital lesions. Cofactors are required for cancer development.

Host Defenses

The roles of humoral and cell-mediated immune responses in disease pathogenesis or prevention are not known. Warts tend to regress spontaneously.

Epidemiology

Papillomaviruses are widely distributed. Transmission occurs by contact. Genital warts are sexually transmitted. Laryngeal papillomas may be due to human papillomavirus acquired during birth from a mother with genital warts. Prevalence data are incomplete, and there are no serologic assays to distinguish the different types.

Diagnosis

Clinically, nucleic acid hybridization may be used to detect viral DNA in tissue samples. Serologic methods need to be developed to identify specific human papillomavirus types.

Control

Instruments should be sterilized after examination of patients with human papillomavirus infections. The public should be educated about this disease to prevent sexual transmission. Most warts regress spontaneously. Available treatments include local destructive methods and application of caustic agents. Interferons are effective against laryngeal papillomas, common warts, and anogenital warts.

Introduction

The term “papovavirus” was derived from the first two letters of the names of three members of this group: pa pillomavirus, mouse po lyoma virus, and simian va cuolating virus (SV40). Members of this group can induce tumors in susceptible hosts and transform the morphologic characteristics of cells in culture.

Structure

Papovaviruses are small, nonenveloped, icosahedral viruses that contain circular, double-stranded DNA. Viral particles range in diameter from 45 to 55 nm. Papovaviruses contain a limited amount of genetic information (six or seven genes); the DNA has a molecular weight of 3 × 106 to 5 × 106. Two or three polypeptides are used to construct the icosahedral capsid that packages the genomic DNA. Cellular histones are incorporated into virions in close association with viral DNA, probably to aid in condensing the DNA inside the capsid.

Classification and Antigenic Types

Papovaviruses are divided into two genera, Polyomavirus and Papillomavirus, on the basis of physicochemical and biologic properties (Table 66-1).

Table 66-1. Properties of Papovaviruses.

Table 66-1

Properties of Papovaviruses.

Polyomaviruses

Polyomaviruses, which are smaller than papillomaviruses, are about 45 nm in diameter and have a genome of approximately 3 × 106 daltons (approximately 5,200 bp). These viruses tend to induce persistent, apparently harmless infections in their natural hosts. They have attracted the attention of research scientists because they induce tumors when injected into rodents. In addition, because of their small genetic content, the polyomaviruses have served as simple model systems for exploring the molecular events in transformation and other mammalian cell biologic processes. One of the SV40 early gene products, the large tumor antigen (T antigen), is required for viral DNA replication during productive infection and for initiation and maintenance of the transformed phenotype. Two polyomaviruses, BK virus and JC virus, are found in humans. The human and animal polyomaviruses all are antigenically distinct. Only one serotype is known for each agent.

The genome of simian virus 40 (SV40), a polyomavirus that has been intensively studied, is diagrammed in Figure 66-1. The genetic structure of the human viruses in this genus, JC and BK viruses, closely resembles that of SV40. The polyoma virus of mice differs only in that it codes for an additional early gene product. The entire nucleotide sequences of several papovavirus DNAs have been determined. About half of the SV40 genome encodes nonstructural proteins that are expressed before viral DNA synthesis begins. The products of that region are designated early functions. The early proteins also are referred to as tumor antigens because they were first detected in virus-induced tumors by using sera from tumor-bearing animals. The other half of the viral genome codes for virion structural proteins, which are called late functions because they are expressed after viral DNA synthesis begins. The structural proteins make up the protein coat of the viral particles.

Figure 66-1. Physical and functional map of the SV40 genome (genus Polymavirus).

Figure 66-1

Physical and functional map of the SV40 genome (genus Polymavirus). The thick circle represents the circular SV40 DNA genome. The unique Eco RI site is shown at map unit 1/0. (more...)

Image ch66fu1.jpg
MULTIPLICATION

These viruses make maximum use of their limited amount of genetic information. Some of the virus-encoded proteins are encoded partly by shared regions of the DNA (e.g., VP2 and VP3; small t and large T antigens). Other proteins are translated from different reading frames from overlapping regions of the DNA (e.g., VP2 and VP1) (Fig. 66-1).

The two known human polyomaviruses have been studied extensively. BK virus was isolated from the urine of a recipient of a renal allograft who was undergoing immunosuppressive therapy, whereas JC virus was recovered from the brain tissue of a patient with progressive multifocal leukoencephalopathy, a rare demyelinating disease. The two viruses are antigenically distinct from each other and from other members of the Polyomavirus genus, but the early proteins (tumor antigens) induced by BK and JC viruses have some of the same antigenic determinants as those of SV40.

Papillomaviruses

The papillomaviruses are slightly larger than the polyomaviruses, with a more complex circular DNA genome (Table 66-1). In contrast to the polyomaviruses, the papillomaviruses induce tumors in their natural hosts. Papillomaviruses have been found in many species, including humans, rabbits, cows, and dogs. They are highly species specific and are not known to cross the host species barriers. They are associated with a variety of benign papillomatous lesions of the skin and squamous mucosa.

The genome organization of the papillomaviruses differs significantly from that of the polyomaviruses (Fig. 66-2). Studies have been impeded by the lack of a tissue culture system that is able to support papillomavirus replication in vitro. However, recombinant DNA technology has been used to clone several papillomavirus genomes. Nucleotide sequence analyses have revealed at least six open reading frames. Two are “late” open reading frames that encode capsid proteins; others are “early” open reading frames that are involved in viral replication and cellular transformation.

Figure 66-2. Map of the human papillomavirus type 16 genome (genus Papillomavirus).

Figure 66-2

Map of the human papillomavirus type 16 genome (genus Papillomavirus). The DNA is circular, but is shown linearized in the noncoding region (NCR). The genome is marked in kilobase pairs (more...)

Papillomaviruses cannot be cultured in vitro, and no serologic reagents are available to distinguish human isolates. Human papillomavirus types are distinguished on the basis of DNA homology. Each type shares less than 50 percent homology with all other recognized types under stringent DNA hybridization conditions. A new definition of genotypes, based on DNA sequence data, is that two types differ 10 percent or more in the nucleotides in the L1, E6, and E7 sequences. More than 70 different types have been identified, each of which tends to be associated with specific pathologic conditions.

Papillomavirus isolates from different animal species are serologically distinct. Antisera prepared against intact viral particles are type specific and will not react with tissues infected by another type of papillomavirus, but antisera against virions disrupted by detergent cross-react with capsid antigens of all papillomaviruses, including those from other species. This reflects the presence of conserved sequences in papillomavirus structural proteins that are not exposed on the surface of viral particles.

Virus Multiplication and Cell Transformation

Papovaviruses undergo two types of interactions with host cells (Fig. 66-3). Permissive cells support viral replication, which results in the synthesis of progeny virus and cell death (lysis). Nonpermissive cells do not support viral replication but can be transformed. Permissive cells can, on rare occasions, be transformed if viral replication is incomplete, such as when a defective virus infects a cell. When cells are transformed, the cells survive, the cellular phenotype is altered, and no progeny virus is produced. Most of our knowledge of viral replication and cell transformation is based on studies with SV40 and mouse polyoma virus. The expression of SV40-specific events in lytic and in transforming infections is compared in Table 66-2.

Figure 66-3. Schematic comparison of two types of interaction between a papovavirus and a host cell.

Figure 66-3

Schematic comparison of two types of interaction between a papovavirus and a host cell. The productive cycle that results in the synthesis of progeny virions is diagrammed on the left. The transforming (more...)

Table 66-2. Expression of Virus-Induced Events in SV40 Productive and Transforming Infections.

Table 66-2

Expression of Virus-Induced Events in SV40 Productive and Transforming Infections.

Polyomaviruses

The polyomaviruses have a narrow host range. Permissive cells are derived from the natural host of each isolate (monkey cells for SV40, mouse cells for polyoma virus, and human cells for BK and JC viruses). Not all cell types from the susceptible species will support viral replication.

The infecting virion first attaches to specific receptors on permissive cells, then penetrates the plasma membrane and is transported to the nucleus, where the viral DNA is uncoated and released. During the early phase of the lytic cycle, the virus drives the cell into the S phase, thereby providing cellular enzymes associated with DNA metabolism, such as thymidine kinase and DNA polymerase. The virus uses the cellular enzymes for its own replication, as the polyomavirus genetic content is too limited to encode all of the necessary replicative functions. The induction of host cell synthetic processes depends on the expression of the early portion of the viral genome and the synthesis of large T antigen. The large T antigen binds cellular tumor suppressor proteins p53 and Rb and disrupts their normal cell cycle regulatory functions.

The early proteins (tumor antigens) are synthesized soon after infection and reach detectable levels at about 12 to 15 hours after infection. Viral DNA synthesis begins shortly after that time. The large T antigen is a prerequisite for viral DNA replication. It binds to viral DNA at the site of initiation of DNA synthesis and is essential for viral replication in permissive cells. DNA replication proceeds bidirectionally from the unique origin site. The expression of late viral genes occurs after DNA synthesis begins. Early RNA is transcribed from half of one strand of viral DNA (E strand), whereas late viral RNA is transcribed from the other half of the genome, using the opposite strand of DNA (L strand) as a template (Fig. 66-1). T antigen binding initiates transcription of late viral RNA in addition to initiating viral DNA replication.

The structural viral proteins VP1, VP2, and VP3 are synthesized from late viral mRNA and are transported into the nucleus. Progeny virions are assembled and accumulate in the nucleus, becoming detectable by 24 hours after infection. Eventually the host cells are killed. As a group, the papovaviruses have the longest (slowest) growth cycle of the DNA viruses. Cell lysis usually does not occur until 40 to 48 hours after infection. Progeny viral particles are frequently not efficiently released from cell debris.

An important biologic property of the polyomaviruses is their ability to transform cells (i.e., to convert normal cells into tumor cells). Because transformation requires cell survival and multiplication, it is not compatible with lytic (productive) infections. Transforming infections are basically abortive and may result either from viral infection of nonpermissive cells or from the infection of permissive cells with defective viral genomes (Fig. 66-3). Permanent transformation by a polyomavirus is very rare (see Ch. 47).

The virus-induced early events that are expressed in permissive cells also occur in nonpermissive cells (Table 66-2). Tumor antigens are synthesized, cell regulatory proteins are bound, and cellular DNA synthesis is stimulated. However, no free viral DNA synthesis occurs, and late viral genes that encode capsid proteins are not expressed. The viral genome becomes integrated in the cellular chromosome. Integration of viral sequences into host cell DNA is random and can occur at many different sites. In general, only one or a very few viral DNA copies are present in an individual transformed cell. The entire viral genome need not be retained in transformed cells, but an intact early region is required because the transforming protein (the large T antigen) must be synthesized continuously for a cell to remain transformed.

Viral transformation and tumor induction involve two or more separate viral functions. One event is responsible for cell immortalization (unlimited cell proliferation), whereas another event mediates structural and behavioral changes characteristic of the transformed phenotype. The large T antigen is the critical gene product in the SV40 system. The ability of large T antigen to bind cellular p53 and Rb family proteins is required for SV40 transforming activity. In transformed cells, the large T antigen localizes predominantly in the nucleus, although a small fraction (no more than 5 percent) is associated with the plasma membrane, where it is involved in virus-specific transplantation antigen reactions. In the mouse polyoma virus system, two early proteins have a role in carrying out transforming functions. Immortalization of primary cells is mediated by the large T antigen, which is localized in the nucleus. However, those cells remain phenotypically normal. In contrast, the polyoma virus middle T antigen (which associates with the plasma membrane) transforms immortalized cells, but is not able to alter primary cells. Middle T antigen binds cellular proteins, including c-src, and alters cellular growth signal transduction events.

Transformation is a stable, inherited change in cell properties. The most prominent phenotypic modifications associated with SV40-transformed cells include altered morphology (more rounded); altered growth patterns (increased growth rate, decreased requirement for serum growth factors, loss of contact inhibition, and enhanced ability to grow in semisolid medium [anchorage independence]); biochemical changes (increased metabolic rate, increased glycolysis, changes in properties of the cell membrane, synthesis of new antigens in the cell); and tumorigenicity (production of tumors when transformed cells are injected into appropriate test animals).

Papillomaviruses

Papillomaviruses have a high tropism for epithelial cells of the skin and mucous membranes. Replication of the viruses depends strongly on the differentiated state of the cell. When present, progeny virions can be detected only in nuclei of cells in the upper layers of the infected epidermis (Fig. 66-4). Viral nucleic acid is maintained in basal cells at low copy numbers, where it replicates in synchrony with the cell cycle. Vegetative viral DNA synthesis occurs predominantly in the stratum spinosum and the stratum granulosum, and capsid protein expression is restricted to the uppermost layer of terminally differentiated epidermal cells. Viral particles can be detected easily in some types of warts (e.g., hand and plantar warts), but may not be found in other types of lesions (e.g., those of the larynx, external genitalia, and cervix). Certain events in the viral life cycle presumably depend on cellular factors present in specific differentiated states of epithelial cells. This dependence of viral replication on cell differentiation is responsible for the failure of researchers to obtain a reproducible tissue culture system that is permissive for papillomavirus replication or transformation.

Figure 66-4. Schematic representation of a skin wart (papilloma).

Figure 66-4

Schematic representation of a skin wart (papilloma). The papillomavirus life cycle is tied to epithelial cell differentiation. The terminal differentiation pathway of epidermal cells is shown (more...)

Regulation of gene expression in papillomaviruses is much more complex than in polyomaviruses. Viral DNA remains episomal (free) in benign lesions, whereas it is integrated into host chromosomal DNA in malignant cells (e.g., cervical carcinoma). The E6 and E7 open reading frames are the transforming genes; both are required for cell transformation.

The papillomaviruses induce benign tumors (warts) of the epithelium in their natural hosts. A few types are associated with carcinoma development. This expression of oncogenic potential in natural hosts is in marked contrast to the actions of the polyomaviruses, which do not cause tumors in natural hosts. The papillomaviruses have a narrow host range; no interspecies transmission has been documented.

Polyomaviruses

Clinical Manifestations

The polyomaviruses establish persistent, harmless infections in their natural hosts. BK virus has not been proven to cause any clinical disease.

JC virus is presumed to cause progressive multifocal leukoencephalopathy, a rare disease due to an opportunistic JC virus infection of individuals with impaired immunity. Large numbers of viral particles are present within the nuclei of glial cells in the brain lesions of patients with progressive multifocal leukoencephalopathy. The onset of the disease is insidious. Early signs include abnormalities of speech and vision and alterations in mental function. The disease is progressive, culminating in coma and death, usually within 6 months of onset.

Pathogenesis

Both human polyomaviruses are ubiquitous among humans, with the initial infection occurring during childhood. Primary infections must include a viremic phase, because both BK and JC viruses persist in the kidneys of healthy individuals after the primary infection and may reactivate when the host immune response is impaired. It is not known whether JC virus reaches the brain during primary infection and persists there in a latent form until reactivated by immunosuppression, or whether it invades the brain after reactivation of a persistent infection at a distant site, such as the kidneys. Progressive multifocal leukoencephalopathy sometimes develops in AIDS patients. The distinctive features of this disease are the presence of altered oligodendrocytes containing many papovavirus particles in their nuclei and the presence of giant astrocytes with hyperchromatic nuclei. Demyelination occurs because JC virus causes a lytic infection of the oligodendrocytes. In advanced lesions, oligodendrocytes are absent because of cell necrosis.

BK virus is often activated in renal transplant patients and in others who have received immunosuppressive agents, and it is excreted in the urine. Several cases of papovavirus-associated obstruction of the ureter have been described in renal allograft recipients. In addition BK virus has been recovered from the urine of patients with hereditary immunodeficiency diseases, such as the Wiskott-Aldrich syndrome. Both BK and JC viruses may be reactivated and excreted in urine during normal pregnancies.

SV40 seems to localize in the urinary tract of its natural host, the rhesus monkey, but tumor induction in the monkey has not been observed. Early lots of live poliomyelitis vaccines that had been produced in monkey cells were contaminated with SV40. Many persons inadvertently received such SV40-contaminated vaccines 25 years ago, but none have been reported to have developed SV40-related tumors. SV40 DNA has been detected in some human brain tumors, but whether the virus caused the tumors is unknown. Although wild mice harbor polyoma virus, tumors do not result from natural infections. The virus probably is transmitted through urine, feces, and saliva. The oncogenic potential of the polyomaviruses can be demonstrated only by experimental inoculation of certain heterologous newborn animals (hamsters for SV40; mice, rats, and hamsters for polyoma virus).

Host Defenses

The polyomavirus members of the papovavirus group produce asymptomatic, persistent infections in their natural hosts. They elicit an antibody response that can be detected serologically by, for example, neutralization or hemagglutination-inhibition assays. BK and JC viruses have often been isolated from immunosuppressed individuals, indicating that their expression is under the control of the immunologic system. Impaired cell-mediated immunity is associated with virus reactivation and appears to be a determining factor in the development of progressive multifocal leukoencephalopathy. In contrast, patients with progressive multifocal leukoencephalopathy commonly have normal levels of serum antibody to JC virus.

The immune response of animals with tumors induced by polyomaviruses or SV40 has been studied extensively. Tumor-bearing animals develop antibodies against the virus-specific tumor antigens involved in the maintenance of the transformed phenotype. In addition, cellular immunity develops against virus-induced, tumor-specific transplantation antigens that are located at the cell membrane. This immunity renders the animals resistant to challenge with tumor cells. These rodent model systems afford an opportunity for understanding more about the immune response to neoplastic cells in humans.

Epidemiology

Seroepidemiologic studies have shown that BK and JC viruses occur worldwide. Infections occur early in childhood, and 70 to 80 percent of adults have antibodies to these viruses. Little is known about the routes of infection, but the spread in early childhood and the high infection rates suggest respiratory transmission. Although a low percentage of pregnant women shed BK or JC virus in their urine, especially during the third trimester, there is no indication of transplacental transmission and congenital infection by either virus. Both JC and BK viruses appear to be strictly human viruses, with no animal reservoirs.

The prevalence of SV40 infections in humans today is not known, although many persons were exposed to the virus when they received contaminated poliovirus vaccines in the late 1950's.

Diagnosis

Primary isolation of human polyomaviruses is too difficult to be attempted outside of specialized research laboratories. Viral DNA can be detected in suspect tissues by polymerase chain reaction or nucleic acid hybridization, and tissues and body fluids may be examined by electron microscopy to detect papovavirus particles. The hemagglutination-inhibition test is useful for serodiagnosis of JC and BK virus infections.

Control

No control measures for human polyomavirus infections are currently available. As they are not linked to important human disease, there is no incentive to attempt to prevent infections in the general population. No effective treatments exist for progressive multifocal leukoencephalopathy. Reduction in immunosuppression would appear to offer the best opportunity for slowing the progression of this disease.

Papillomaviruses

Clinical Manifestations

A variety of benign papillomatous lesions of the skin and squamous mucosa are caused by human papillomaviruses. These include common and plantar warts, flat warts, anal and genital condylomata acuminata, cervical flat warts, macular pityriasis-like lesions in patients with epidermodysplasia verruciformis, oral papillomas, and juvenile laryngeal papillomas. The laryngeal papillomas can be dangerous because they occur in young children, tend to cause acute respiratory obstruction, and often recur.

Papillomavirus infections may be subclinical. The most common clinical changes in both males and females are condylomata acuminata (anogenital warts). Papillomavirus infections occur throughout the lower female genital tract. Multiple sites are often involved, including on the cervix, in the vagina, and in the vulvar region. In addition, lesions called cervical intraepithelial neoplasia are associated with human papillomavirus infection. These lesions are believed to reflect mild-to-moderate cervical dysplasia and are typified by large round cells called koilocytes. In men, anal condylomas and penile warts occur separately or together.

Epidermodysplasia verruciformis is a rare cutaneous disease characterized by disseminated lesions resembling flat warts and reddish macules.

Most papillomavirus-induced lesions are entirely benign and are not correlated with malignant transformation. However, certain human papillomavirus-associated anogenital lesions may progress to squamous cell carcinomas. In addition, epidermodysplasia verruciformis patients may develop skin carcinomas, and rare cases of laryngeal papillomatosis become malignant.

Pathogenesis

Papillomaviruses induce benign papillomas of the skin and squamous mucosa. Viruses are transmitted by contact and enter the body through minute abrasions in the skin. Cell growth control is disrupted, resulting in thickening of the epidermis with hyperplasia in the stratum spinosum and some degree of hyperkeratosis. Basophilic intranuclear inclusion bodies often occur in the stratum granulosum. The basement membrane remains intact.

Different human papillomavirus types cause distinct pathologic lesions (Table 66-3), although exceptions do occur. A few specific types are strongly associated with the development of premalignant and malignant genital disease. More than 90 percent of cervical cancers worldwide are positive for papillomavirus DNA, about half of which are type 16. Many precancerous cervical intraepithelial neoplasias, as well as penile and vulvar cancers, also carry human papillomavirus DNA. Viral DNA has also been detected in cancers of the larynx, oropharynx, and tongue. On the basis of the relative occurrence of viral DNA in certain cancer tissues, human papillomavirus types are found to vary in oncogenic potential. Types 16 and 18 are considered to pose a high cancer risk; type 31, intermediate risk; and types 6 and 11, low risk. Many other types are considered benign. For this reason, it will become important to identify the specific type present in a clinical lesion.

Table 66-3. Association of Human Papillomavirus Types with Clinical Lesions.

Table 66-3

Association of Human Papillomavirus Types with Clinical Lesions.

Laryngeal papillomas in children are caused by human papillomavirus types 6 and 11. It is believed the infection is acquired during passage through an infected birth canal, because infants with laryngeal papillomas are often born to mothers with genital condylomas.

Viral DNA is commonly found in epithelial cells surrounding a given lesion. Cofactors are most probably involved in the progression of high-risk human papillomavirus lesions to carcinomas. Suspected cofactors include irradiation, carcinogenic products of tobacco smoke, and genital infection by herpes simplex virus.

Host Defenses

Host immune responses to papillomavirus infections are not well understood. In general, warts persist for variable periods and then regress. The host is probably immune to reinfection with the same virus. The respective roles of humoral and cellular immunity in this response are not known. Cell-mediated immunity is probably important, as immunosuppressed patients experience an increased incidence of warts. Among immunocompetent individuals, about one-third of the warts will regress within 2 months of appearance, two-thirds will disappear within a year, and all will be gone within 5 years.

Papovaviruses are generally poor inducers of interferon and vary greatly in their susceptibility to its antiviral action.

Epidemiology

Papillomaviruses are widely distributed in humans. Epidemiologic studies have been limited by the lack of suitable assays and the existence of multiple virus types.

Transmission of human papillomavirus occurs by direct contact with another infected person, by autoinoculation (e.g., common warts spread by scratching), or by indirect contact (e.g., plantar warts acquired in showers). Genital warts are sexually transmitted. Estimates of the rate of papillomavirus genital infections in the general population, based on studies of small groups, have ranged from 2 to 13 percent for women in western Europe to more than 30 percent for women in Latin America.

Strong epidemiologic evidence suggests that a sexually transmitted infectious agent is involved in the etiology of cervical cancer. This is compatible with the evidence that human papillomavirus is a factor in the development of genital cancers. At least 90 percent of cervical cancers contain human papillomavirus DNA, predominantly type 16 or 18. The prevalence of type 16 infections is about 10 times that of type 18 infections. It appears that progression of precancerous lesions to cancer is higher with type 16 than with other types.

Diagnosis

Papillomavirus infections are usually clinically recognizable. Because in vitro culture methods are not available, diagnostic procedures are based on biochemical assays. Molecular hybridization or polymerase chain reaction may be used to detect viral DNA in samples, and serologic reagents may detect capsid antigens in tissues. The latter is not very useful, as the number of antigen-producing cells in a lesion is usually small. Because of the differing oncogenic potential of human papillomavirus types, it is important that methods be developed to identify specific virus types in clinical lesions.

Control

Cross-infection can be prevented by avoiding the sharing of towels, shower shoes, and dressings. Correct sterilization of all instruments used for examining and treating patients with human papillomavirus infection is very important. Papillomaviruses are stable, and infectivity can survive improper sterilization procedures. General principles for the control of sexually transmitted diseases apply to human papillomavirus infection, including health education to avoid casual sex, to use condoms, and to seek medical attention for lesions.

There is no generally effective treatment for all warts. Most warts regress spontaneously, but patients will seek treatment for cosmetic purposes or because of discomfort. Available treatment modalities consist of locally destructive techniques, such as cautery, surgical excision, and cryotherapy with liquid nitrogen. Caustic agents (podophyllin, trichloroacetic acid) may be applied directly to lesions. Interferons have given good clinical responses against laryngeal papillomas and skin and anogenital warts. Antiviral drugs, such as idoxuridine and acyclovir, are ineffective. Condylomata and laryngeal papillomas tend to recur after treatment.

The aim of treatment of dysplastic lesions is to prevent invasive cancer. Local destructive methods are used.

The high prevalence of papillomavirus infections and their association with cancer make these viruses candidates for vaccine development. Evidence from a canine model suggests that an inactivated vaccine may protect against subsequent mucosal infection. However, successful vaccine development for humans requires a better understanding of both the host immune response to human papillomavirus infection and the epidemiology of different virus types.

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