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43 C H A P T E R Human Cancer Viruses...

43 C H A P T E R Human Cancer Viruses Viruses are etiologic factors in the development of sev- genome and the biophysical characteristics of their virions. eral types of human tumors, including two of great signifi- Most recognized tumor viruses either have a DNA genome or cance worldwide—cervical cancer and liver cancer. At least generate a DNA provirus after infection of cells (hepatitis C 15–20% of all human tumors worldwide have a viral cause. virus is an exception). The viruses that have been strongly associated with human DNA tumor viruses are classified among the papilloma-, cancers are listed in Table 43-1. They include human papillo- polyoma-, adeno-, herpes-, hepadna-, and poxvirus groups. maviruses (HPVs), Epstein-Barr virus (EBV), human herpes- DNA tumor viruses encode viral oncoproteins that are virus 8, hepatitis B virus, hepatitis C virus, and two human important for viral replication but also affect cellular growth retroviruses plus several candidate human cancer viruses. control pathways. New cancer-associated viruses are being discovered by the Most RNA tumor viruses belong to the retrovirus fam- use of molecular techniques. Many viruses can cause tumors ily. Retroviruses carry an RNA-directed polymerase (reverse in animals, either as a consequence of natural infection or transcriptase) that constructs a DNA copy of the RNA after experimental inoculation. genome of the virus. The DNA copy (provirus) becomes inte- Animal viruses are studied to learn how a limited grated into the DNA of the infected host cell, and it is from amount of genetic information (one or a few viral genes) this integrated DNA copy that all proteins of the virus are can profoundly alter the growth behavior of cells, ultimately translated. converting a normal cell into a neoplastic one. Such studies RNA tumor viruses are of two general types with respect reveal insights into growth regulation in normal cells. Tumor to tumor induction. The highly oncogenic (direct-transforming) viruses are agents that can produce tumors when they infect viruses carry an oncogene of cellular origin. The weakly appropriate animals. Many studies are done using cultured oncogenic (slowly transforming) viruses do not contain an animal cells rather than intact animals, because it is possible oncogene and induce leukemias after long incubation peri- to analyze events at cellular and subcellular levels. In such ods by indirect mechanisms. The two known cancer-causing cultured cells, tumor viruses can cause “transformation.” retroviruses in humans act indirectly. Hepatitis C virus, a fla- However, animal studies are essential to studying many steps vivirus, does not generate a provirus and appears to induce in carcinogenesis, including complex interactions between cancer indirectly. virus and host and host responses to tumor formation. Studies with RNA tumor viruses revealed the involve- ment of cellular oncogenes in neoplasia; DNA tumor viruses established a role for cellular tumor suppressor genes. Multistep Carcinogenesis These discoveries revolutionized cancer biology and pro- Carcinogenesis is a multistep process; that is, multiple vided the conceptual framework for the molecular basis of genetic changes must occur to convert a normal cell into a carcinogenesis. malignant one. Intermediate stages have been identified and designated by terms such as “immortalized,” “hyperplastic,” and “preneoplastic.” Tumors usually develop slowly over GENERAL FEATURES OF VIRAL a long period of time. The natural history of human and CARCINOGENESIS animal cancers suggests a multistep process of cellular evolution, probably involving cellular genetic instability and Tenets of viral carcinogenesis are summarized in Table 43-2. repeated selection of rare cells with some selective growth advantage. The number of mutations underlying this pro- cess is estimated to range from five to eight. Observations Tumor Viruses Are of Different Types suggest that activation of multiple cellular oncogenes and Like other viruses, tumor viruses are classified among dif- inactivation of tumor suppressor genes are involved in the ferent virus families according to the nucleic acid of their evolution of tumors whether or not a virus is involved. 635 Riedel_CH43_p635-p654.indd 635 04/04/19 5:11 PM  636   SECTION IV  Virology TABLE 43-1 Association of Viruses with Human MOLECULAR MECHANISMS Cancersa OF CARCINOGENESIS Virus Family Virus Human Cancer Cellular Oncogenes Papillomaviridae Human Genital tumors papillomaviruses Squamous cell “Oncogene” is the general term given to genes that are carcinoma involved in cancer causation. Normal versions of these trans- Oropharyngeal forming genes are present in normal cells and have been des- carcinoma ignated proto-oncogenes. Herpesviridae Epstein-Barr virus Nasopharyngeal The discovery of cellular oncogenes came from studies carcinoma with acutely transforming retroviruses. It was found that nor- Burkitt lymphoma Hodgkin’s disease mal cells contained highly related (but not identical) copies of B-cell lymphoma various retrovirus transforming genes; cellular sequences had Human herpesvirus 8 Kaposi sarcoma been captured and incorporated into the retrovirus genomes. Primary effusion Transduction of the cellular genes was probably an accident, lymphoma as the presence of the cellular sequences is of no benefit to the Hepadnaviridae Hepatitis B virus Hepatocellular viruses. Many other known cellular oncogenes that have not carcinoma been segregated into retrovirus vectors have been detected using molecular methods. Polyomaviridae Merkel cell virus Merkel cell carcinoma Cellular oncogenes are partly responsible for the molec- ular basis of human cancer. They represent individual com- Retroviridae Human Adult T-cell T-lymphotropic leukemia ponents of complicated pathways responsible for regulating virus cell proliferation, division, and differentiation and for main- taining the integrity of the genome. Incorrect expression of Human AIDS-related immunodeficiency malignancies any component might interrupt that regulation, resulting virus in uncontrolled growth of cells (cancer). Examples exist of tyrosine-specific protein kinases (eg, src), growth factors (sis Flaviviridae Hepatitis C virus Hepatocellular carcinoma is similar to human platelet-derived growth factor, a potent mitogen for cells of connective tissue origin), mutated growth Candidate human tumor viruses include additional types of papillomaviruses and a factor receptors (erb-B is a truncated epidermal growth factor polyomaviruses. receptor), GTP-binding proteins (Ha-ras), and nuclear tran- It appears that a tumor virus usually acts as a cofactor, scription factors (myc, jun). providing only some of the steps required to generate malig- The molecular mechanisms responsible for activating a nant cells. Viruses are necessary—but not sufficient—for benign proto-oncogene and converting it into a cancer gene development of tumors with a viral etiology. Viruses often vary—but all involve genetic damage. The gene may be over- act as initiators of the neoplastic process and may do so by expressed, and a dosage effect of the overproduced oncogene different mechanisms. product may be important in cellular growth changes. These mechanisms might result in constitutive activity (loss of nor- mal regulation), so that the gene is expressed at the wrong TABLE 43-2 Tenets of Viral Carcinogenesis time during the cell cycle or in inappropriate tissue types. 1. Viruses can cause cancer in animals and humans Mutations might alter the carefully regulated interaction 2. Tumor viruses frequently establish persistent infections in of a proto-oncogene protein with other proteins or nucleic natural hosts 3. Host factors are important determinants of virus-induced acids. Insertion of a retroviral promoter adjacent to a cellular tumorigenesis oncogene may result in enhanced expression of that gene (ie, 4. Viruses are seldom complete carcinogens “promoter-insertion oncogenesis”). Expression of a cellular 5. Virus infections are more common than virus-related tumor gene also may be increased through the action of nearby viral formation 6. Long latent periods usually elapse between initial virus infection “enhancer” sequences. and tumor appearance 7. Viral strains may differ in oncogenic potential 8. Viruses may be either direct- or indirect-acting carcinogenic agents Tumor Suppressor Genes 9. Oncogenic viruses modulate growth control pathways in cells A second class of human cancer genes is involved in tumor 10. Animal models may reveal mechanisms of viral carcinogenesis development. These are the negative regulators of cell growth, 11. Viral markers are usually present in tumor cells 12. One virus may be associated with more than one type of tumor tumor suppressor genes. They were identified because they form complexes with oncoproteins of certain DNA tumor Reproduced with permission from Butel JS: Viral carcinogenesis: Revelation of molecular mechanisms and etiology of human disease. Carcinogenesis 2000;21:405. viruses. The inactivation or functional loss of both alleles of By permission of Oxford University Press. such a gene is required for tumor formation—in contrast to Riedel_CH43_p635-p654.indd 636 04/04/19 5:11 PM  CHAPTER 43 Human Cancer Viruses   637 the activation that occurs with cellular oncogenes. The pro- individuals are at increased risk of EBV-associated lympho- totype of this inhibitory class of genes is the retinoblastoma mas and of HPV-related diseases. It is possible that variations (Rb) gene. The Rb protein inhibits entry of cells into S phase in individual immune responses may contribute to suscepti- by binding to key transcription factors that regulate expres- bility to virus-induced tumors in normal hosts. sion of S-phase genes. The function of normal Rb protein is regulated by phosphorylation. The loss of Rb gene function is causally related to the development of retinoblastoma—a rare Mechanisms of Action by Human ocular tumor of children—and other human tumors. Cancer Viruses Another crucial tumor suppressor gene is the p53 gene. It Tumor viruses mediate changes in cell behavior by means of also blocks cell cycle progression; p53 acts as a transcription a limited amount of genetic information. There are two gen- factor and regulates the synthesis of a protein that inhibits the eral patterns by which this is accomplished: The tumor virus function of certain cell cycle kinases. It also causes cells with introduces a new “transforming gene” into the cell (direct- DNA damage to undergo apoptosis. The loss of p53 function acting), or the virus alters the expression of a preexisting cel- allows cells with damaged DNA to progress through the cell lular gene or genes (indirect-acting). In either case, the cell cycle, leading to the eventual accumulation of genetic muta- loses control of normal regulation of growth processes. DNA tions. The p53 gene is mutated in over half of all human repair pathways are frequently affected, leading to genetic cancers. instability and a mutagenic phenotype. Viruses usually do not behave as complete carcinogens. In addition to changes mediated by viral functions, other INTERACTIONS OF TUMOR VIRUSES alterations are necessary to disable the multiple regulatory WITH THEIR HOSTS pathways and checkpoints in normal cells to allow a cell to become completely transformed. There is no single mode Persistent Infections of transformation underlying viral carcinogenesis. At the The pathogenesis of a viral infection and the response of the molecular level, oncogenic mechanisms by human tumor host are integral to understanding how cancer might arise viruses are very diverse. from that background. The known tumor viruses establish Cellular transformation may be defined as a stable, heri- long-term persistent infections in humans. Because of differ- table change in the growth control of cells in culture. No set ences in individual genetic susceptibilities and host immune of characteristics invariably distinguishes transformed cells responses, levels of virus replication and tissue tropisms may from their normal counterparts. In practice, transformation vary among persons. Even though very few cells in the host is recognized by the cells’ acquisition of some growth prop- may be infected at any given time, the chronicity of infection erty not exhibited by the parental cell type. Transformation presents the long-term opportunity for a rare event to occur to a malignant phenotype is recognized by tumor formation that allows survival of a cell with growth control mechanisms when transformed cells are injected into appropriate test that are virus-modified. animals. Indirect-acting tumor viruses are not able to transform cells in culture. Host Immune Responses Viruses that establish persistent infections must avoid detec- tion and recognition by the immune system that would elimi- Cell Susceptibility to Viral Infections and nate the infection. Different viral evasion strategies have been Transformation identified, including restricted expression of viral genes that At the cellular level, host cells are either permissive or non- makes infected cells nearly invisible to the host (EBV in permissive for replication of a given virus. Permissive cells B cells), infection of sites relatively inaccessible to immune support viral growth and production of progeny virus; non- responses (HPV in the epidermis), mutation of viral anti- permissive cells do not. Especially with the DNA viruses, gens that allows escape from antibody and T-cell recogni- permissive cells are often killed by virus replication and are tion (human immunodeficiency virus [HIV]), modulation of not transformed unless the viral replicative cycle that results host major histocompatibility complex class I molecules in in death of the host cell is blocked in some way; nonpermis- infected cells (adenovirus, cytomegalovirus), inhibition of sive cells may be transformed. However, there are situations antigen processing (EBV), and infection and suppression of in which DNA virus replication does not lyse the host cell and essential immune cells (HIV). such cells may be transformed. Nevertheless, transforma- It is believed that host immune surveillance mechanisms tion is a rare event. A characteristic property of RNA tumor usually eliminate the rare neoplastic cells that may arise in viruses is that they are not lethal for the cells in which they normal individuals infected with cancer viruses. However, if replicate. Cells that are permissive for one virus may be non- the host is immunosuppressed, cancer cells are more likely permissive for another. to proliferate and escape host immune control. Immuno- Not all cells from the natural host species are susceptible suppressed organ transplant recipients and HIV-infected to viral replication or transformation or both. Most tumor Riedel_CH43_p635-p654.indd 637 04/04/19 5:11 PM  638   SECTION IV  Virology viruses exhibit marked tissue specificity, a property that TABLE 43-3 Important Properties of Retroviruses probably reflects the variable presence of surface receptors Virion: Spherical, 80–110 nm in diameter, helical nucleoprotein for the virus, the ability of the virus to cause disseminated within icosahedral capsid versus local infections, or intracellular factors necessary for viral gene expression. Composition: RNA (2%), protein (about 60%), lipid (about 35%), carbohydrate (about 3%) Some viruses are associated with a single tumor type, whereas others are linked to multiple tumor types. These dif- Genome: Single-stranded RNA, linear, positive-sense, 7–11 kb, diploid; may be defective; may carry oncogene ferences reflect the tissue tropisms of the viruses. Proteins: Reverse transcriptase enzyme contained inside virions Retention of Tumor Virus Nucleic Acid in a Envelope: Present Host Cell Replication: Reverse transcriptase makes DNA copy from genomic RNA; DNA (provirus) integrates into cellular chromosome; The stable genetic change from a normal to a neoplastic cell provirus is template for viral RNA generally requires the retention of viral genes in the cell. Maturation: Virions bud from plasma membrane Often, but not always, this is accomplished by the integration of certain viral genes into the host cell genome. With DNA Outstanding characteristics: tumor viruses, a portion of the DNA of the viral genome may Infections do not kill cells become integrated into the host cell chromosome. Some- May transduce cellular oncogenes; may activate expression of times, episomal copies of the viral genome are maintained in cell genes tumor cells. With retroviruses, the proviral DNA copy of the Proviruses remain permanently associated with cells and are viral RNA is integrated in the host cell DNA. Genome RNA frequently not expressed copies of hepatitis C virus that are not integrated are main- Many members are tumor viruses tained in tumor cells. In some viral systems, virus-transformed cells may release growth factors that affect the phenotype of neigh- boring uninfected cells, thereby contributing to tumor for- and hematopoietic systems (leukemias, lymphomas) or of mation. It is also possible that as tumor cells collect genetic connective tissue (sarcomas). mutations during tumor growth, the need for the viral genes Important properties of the retroviruses are listed in that drove tumor initiation may become unnecessary and Table 43-3. viral markers will be lost from some cells. Structure and Composition The retrovirus genome consists of two identical subunits of RNA TUMOR VIRUSES single-stranded, positive-sense RNA, each 7–11 kb in size. The reverse transcriptase contained in virus particles is HEPATITIS C VIRUS essential for viral replication. Hepatitis C virus (see Chapter 35), a member of the Retrovirus particles contain the helical ribonucleopro- Flaviviridae family, contains a genome of single-stranded tein within an icosahedral capsid that is surrounded by an RNA 9.4 kb in size. It appears that the majority of infections outer membrane (envelope) containing glycoprotein and become persistent, even in adults. Chronic infection with lipid. Type- or subgroup-specific antigens are associated with hepatitis C virus leads to chronic inflammation and cirrhosis, the glycoproteins in the viral envelope, which are encoded by and is also considered to be a causative factor in hepatocellular the env gene; group-specific antigens are associated with the carcinoma. The development of hepatocellular carcinoma is virion core, which are encoded by the gag gene. likely mediated by a combination of virus and host specific Three morphologic classes of extracellular retrovirus mechanisms. There are over 70 million chronic carriers of particles—as well as an intracellular form—are recognized, hepatitis C virus, with 1–5% of these going on to develop based on electron microscopy. They reflect slightly different hepatocellular carcinoma. Newer directly acting antiviral processes of morphogenesis by different retroviruses. Exam- treatments for hepatitis C have high cure rates and can prevent ples of each are shown in Figure 43-1. the development of cirrhosis and hepatocellular carcinoma. Type A particles occur only intracellularly and appear to be noninfectious. Intracytoplasmic type A particles, 75 nm in diameter, are precursors of extracellular type B RETROVIRUSES viruses. Type B viruses are 100–130 nm in diameter and contain an eccentric nucleoid. The prototype of this group Retroviruses contain an RNA genome and an RNA-directed is the mouse mammary tumor virus, which occurs in “high DNA polymerase (reverse transcriptase). RNA tumor viruses mammary cancer” strains of inbred mice and is found in in this family mainly cause tumors of the reticuloendothelial particularly large amounts in lactating mammary tissue Riedel_CH43_p635-p654.indd 638 04/04/19 5:11 PM  CHAPTER 43 Human Cancer Viruses   639 A B C D E F G H I FIGURE 43-1 Comparative morphology of types A, B, C, and D retroviruses. A: Intracytoplasmic type A particles (representing immature precursor of budding type B virus). B: Budding type B virus. C: Mature, extracellular type B virus. D: Lack of morphologically recognizable intracytoplasmic form for type C virus. E: Budding type C virus. F: Mature, extracellular type C virus. G: Intracytoplasmic type A particle (representing immature precursor form of type D virus). H: Budding type D virus. I: Mature, extracellular type D virus. All micrographs are approximately 87,000×. Thin sections were double-stained with uranyl acetate and lead citrate. (Courtesy of D Fine and M Gonda.) and milk. It is readily transferred to suckling mice, which Classification subsequently develop adenocarcinoma of the breast at high rates. The type C viruses represent the largest group of ret- A. Genera roviruses. The particles are 90–110 nm in diameter, and the The Retroviridae family is divided into seven genera: Alpharet- electron-dense nucleoids are centrally located. The type C rovirus (which contains avian leukosis and sarcoma viruses), viruses may exist as exogenous or endogenous entities (see Betaretrovirus (mouse mammary tumor virus), Gammaretro- as follows). The lentiviruses are also type C viruses. Finally, virus (mammalian leukemia and sarcoma viruses), Deltaret- the type D retroviruses are poorly characterized. The par- rovirus (human T-lymphotropic viruses [HTLV] and bovine ticles are 100–120 nm in diameter, contain an eccentric leukemia virus), Epsilonretrovirus (fish viruses), Spumavirus nucleoid, and exhibit surface spikes shorter than those on (which contains viruses able to cause “foamy” degeneration type B particles. of inoculated cells but which are not associated with any Riedel_CH43_p635-p654.indd 639 04/04/19 5:11 PM  640   SECTION IV  Virology known disease process), and Lentivirus (which encompasses linked to cellular DNA and are present in all somatic and agents able to cause chronic infections with slowly progres- germ cells in the host; (2) endogenous viral genomes are sive neurologic impairment, including HIV; see Chapter 44). transmitted genetically from parent to offspring; (3) the inte- Retroviruses can be organized in various ways depend- grated state subjects the endogenous viral genomes to host ing on their morphologic, biologic, and genetic properties. genetic control; and (4) the endogenous virus may be induced Differences in genome sequences and natural host range are to replicate either spontaneously or by treatment with extrin- frequently used, but antigenic properties are not. Retrovi- sic (chemical) factors. ruses may be grouped morphologically (types B, C, and D); the vast majority of isolates display type C characteristics. D. Host Range The presence or absence of an appropriate cell surface recep- B. Host of Origin tor is a major determinant of the host range of a retrovirus. Retroviruses have been isolated from virtually all vertebrate Infection is initiated by an interaction between the viral species. Natural infections by a given virus are usually lim- envelope glycoprotein and a cell surface receptor. Ecotropic ited to a single species, though infections across species barri- viruses infect and replicate only in cells from animals of the ers may occur. Group-specific antigenic determinants on the original host species. Amphotropic viruses exhibit a broad major internal (core) protein are shared by viruses from the host range (able to infect cells not only of the natural host same host species. All mammalian viruses are more closely but of heterologous species as well) because they recognize related to one another than to those from avian species. a receptor that is widely distributed. Xenotropic viruses can The RNA tumor viruses most widely studied experimen- replicate in some heterologous (foreign) cells but not in cul- tally are the sarcoma viruses of chickens and mice and the tured cells from the natural host. Many endogenous viruses leukemia viruses of mice, cats, chickens, and humans. have xenotropic host ranges. C. Exogenous or Endogenous E. Genetic Content Exogenous retroviruses are spread horizontally and behave as Retroviruses have a simple genetic content, but there is some typical infectious agents. They initiate infection and transfor- variation in the number and type of genes contained. The mation only after contact. In contrast to endogenous viruses, genetic makeup of a virus influences its biologic proper- which are found in all cells of all individuals of a given spe- ties. Genomic structure is a useful way of categorizing RNA cies, gene sequences of exogenous viruses are found only in tumor viruses (Figure 43-2). infected cells. The pathogenic retroviruses all appear to be The standard leukemia viruses (Alpharetrovirus and exogenous viruses. Gammaretrovirus) contain genes required for viral replica- Retroviruses may also be transmitted vertically through tion: gag, which encodes the core proteins (group-specific the germ line. Viral genetic information that is a constant antigens); pro, which encodes a protease enzyme; pol, which part of the genetic constitution of an organism is designated encodes the reverse transcriptase enzyme (polymerase); and as “endogenous.” An integrated retroviral provirus behaves env, which encodes the glycoproteins that form projections like a cluster of cellular genes and is subject to regulatory con- on the envelope of the particle. The gene order in all retrovi- trol by the cell. This cellular control usually results in partial ruses is 5′-gag-pro-pol-env-3′. or complete repression of viral gene expression. Its location Some viruses, exemplified by the human retroviruses in the cellular genome and the presence of appropriate cellu- (Deltaretrovirus and Lentivirus), contain additional genes lar transcription factors determine to a great extent whether downstream from the env gene. One is a transactivating reg- (and when) viral expression will be activated. It is not uncom- ulatory gene (tax or tat) that encodes a nonstructural pro- mon for normal cells to maintain the endogenous viral infec- tein that alters the transcription or translational efficiency tion in a quiescent form for extended periods of time. of other viral genes. The lentiviruses, including HIV, have a Many vertebrates, including humans, possess multiple more complex genome and contain several additional acces- copies of endogenous RNA viral sequences. The endogenous sory genes (see Chapter 44). viral sequences may affect cellular gene expression patterns. Retroviruses with either of these two genomic struc- Endogenous proviruses of mammary tumor virus carried by tures will be replication-competent (in appropriate cells). inbred strains of mice express superantigen activities that Because they lack a transforming (onc) gene, they cannot influence the T-cell repertoires of the animals. transform cells in tissue culture. However, they may have Endogenous viruses are usually not pathogenic for their the ability to transform precursor cells in blood-forming host animals. They do not produce any disease and cannot tissues in vivo. transform cells in culture. (There are examples of disease The directly transforming retroviruses carry an onc caused by replication of endogenous viruses in inbred strains gene. The transforming genes carried by various RNA tumor of mice.) viruses represent cellular genes that have been appropriated Important features of endogenous viruses are as follows: by those viruses at some time in the distant past and incorpo- (1) DNA copies of RNA tumor virus genomes are covalently rated into their genomes (see Figure 43-2). Riedel_CH43_p635-p654.indd 640 04/04/19 5:11 PM  CHAPTER 43 Human Cancer Viruses   641 ALV gag pro RSV gag pro src pol pol env env MLV gag pro pol env MC29 MMTV ∆ gag myc gag pro env pol sag Ha-MSV HTLV gag env ras pro tax pol rex Mo-MSV gag mos HIV gag env vif vpr pro pol nef tat Ab-MLV rev abl ∆ gag vpu 0 2 4 6 8 10 kb 0 2 4 6 8 10 kb A B FIGURE 43-2 Genetic organization of representative retroviruses. A: Nondefective, replication-competent viruses. Examples of retroviruses with simple and complex genomes are shown. An open rectangle shows the open reading frame for the indicated gene. If the rectangles are offset vertically, their reading frames are different. Horizontal lines connecting two rectangles indicate that this segment is spliced out. Simple genomes: ALV, avian leukosis virus (Alpharetrovirus); MLV, murine leukemia virus (Gammaretrovirus); MMTV, mouse mammary tumor virus (Betaretrovirus). Complex genomes: HIV, human immunodeficiency virus type 1 (Lentivirus); HTLV, human T-lymphotropic virus (Deltaretrovirus). B: Viruses carrying oncogenes. Several examples are shown, with the oncogene shaded; all are defective except RSV. Ab-MLV, Abelson murine leukemia virus (abl oncogene) (Gammaretrovirus); Ha-MSV, Harvey murine sarcoma virus (ras oncogene) (Gammaretrovirus); MC29, avian myelocytomatosis virus (myc oncogene) (Alpharetrovirus); Mo-MSV, Moloney murine sarcoma virus (mos oncogene) (Gammaretrovirus); RSV, Rous sarcoma virus (src oncogene) (Alpharetrovirus). The scale for genome sizes is shown at the bottom of each panel. (Modified with permission from Vogt VM: Retroviral virions and genomes. In Coffin JM, Hughes SH, Varmus HE [editors]. Retroviruses. Cold Spring Harbor Laboratory Press, 1997.) Such viruses are highly oncogenic in appropriate host viruses. These defective transforming retroviruses have been animals and can transform cells in culture. With very few the source of many of the recognized cellular oncogenes. exceptions, the addition of the cellular DNA results in the loss of portions of the viral genome. Consequently, the sar- F. Oncogenic Potential coma viruses usually are replication-defective; progeny virus The retroviruses that contain oncogenes are highly onco- is produced only in the presence of helper viruses. The helper genic. They are sometimes referred to as “acute trans- viruses are generally other retroviruses (leukemia viruses), forming” agents because they induce tumors in vivo after which may recombine in various ways with the defective very short latent periods and rapidly induce morphologic Riedel_CH43_p635-p654.indd 641 04/04/19 5:11 PM  642   SECTION IV  Virology transformation of cells in vitro. The viruses that do not carry the viral promoter. In the case of the slow-transforming an oncogene have a much lower oncogenic potential. Disease leukemia viruses, the viral promoter or enhancer element is (usually of blood cells) appears after a long latent period (ie, inserted adjacent to or near the cellular gene in the cellular “slow-transforming”); cultured cells are not transformed. chromosome. Briefly, neoplastic transformation by retroviruses is the result of a cellular gene that is normally expressed at low, carefully regulated levels becoming activated and expressed Replication of Retroviruses constitutively. In the case of the acute transforming viruses, a A schematic outline of a typical retrovirus replication cycle, cellular gene has been inserted by recombination into the viral represented by HTLV, is shown in Figure 43-3. The pol genome and is expressed as a viral gene under the control of gene encodes the unique polymerase (reverse transcriptase) HTLV particle GLUT–1 Receptor RNA Capsid entry cDNA Reverse transcription in viral core dsDNA Integration Nucleus Cytoplasm Cellular DNA Provirus Transcription Maturation mRNA Genomic RNA Assembly Translation Proteins Budding FIGURE 43-3 Overview of human T-lymphotropic virus (HTLV) replication cycle. The virus particle attaches to a cell surface receptor, and the viral capsid enters the cell. The viral reverse transcriptase enzyme produces a DNA copy of the genome RNA within the capsid in the cytoplasm. The DNA enters the nucleus and is integrated at random into cell DNA, forming the provirus. The integrated provirus serves as template for the synthesis of viral transcripts, some of which are unspliced and will be encapsidated as genomic RNAs and others and some of which are spliced and will serve as mRNAs. Viral proteins are synthesized; the proteins and genome RNAs assemble; and particles bud from the cell. Capsid proteins are proteolytically processed by the viral protease producing mature, infectious virions, shown schematically as conversion from a square to an icosahedral core. (Courtesy of SJ Marriott.) Riedel_CH43_p635-p654.indd 642 04/04/19 5:11 PM  CHAPTER 43 Human Cancer Viruses   643 R U5 U3 R poly(A) 5′ 3′ Viral RNA genome gag pro pol env Cell U3 R U5 U3 R U5 Cell Integrated provirus DNA LTR gag pro pol env LTR FIGURE 43-4 Comparison of structures of retrovirus RNA genome and integrated provirus DNA. A virus particle contains two identical copies of the single-stranded RNA genome. The 5′ terminal is capped, and the 3′ terminal is polyadenylated. A short sequence, R, is repeated at both ends; unique sequences are located near the 5′ (U5) and 3′ (U3) ends. U3 contains promoter and enhancer sequences. The integrated provirus DNA is flanked at each end by the long terminal repeat (LTR) structure generated during synthesis of the DNA copy by reverse transcription. Each LTR contains U3, R, and U5 sequences. The LTRs and coding regions of the retrovirus genome are not drawn to scale. protein that has four enzymatic activities (protease, poly- There is no known way to cure a cell of a chronic retrovi- merase, RNase H, and integrase). After virus particles have rus infection. adsorbed to and penetrated host cells, the viral RNA serves as the template for the synthesis of viral DNA through the action of the viral enzyme reverse transcriptase, function- Human Retroviruses ing as an RNA-dependent DNA polymerase. By a complex A. Human T-Lymphotropic Viruses process, sequences from both ends of the viral RNA become Only a few retroviruses are linked to human tumors. The duplicated, forming the long terminal repeat located at each human T-lymphotropic virus (HTLV) group of retrovi- end of the viral DNA (Figure 43-4). Long terminal repeats ruses has probably existed in humans for thousands of are present only in viral DNA. The newly formed viral DNA years. HTLV-1 has been established as the causative agent becomes integrated into the host cell DNA as a provirus. of adult T-cell leukemia-lymphomas (ATL) as well as a ner- The structure of the provirus is constant, but its integra- vous system degenerative disorder called tropical spastic tion into host cell genomes can occur at different sites. The paraparesis. It does not carry an oncogene. Three related very precise orientation of the provirus after integration is human viruses, HTLV-2, HTLV-3, and HTLV-4, have achieved by specific sequences at the ends of both long ter- been isolated but have not been conclusively associated minal repeats. with a specific disease. HTLV-1 and HTLV-2 share about Progeny viral genomes may then be transcribed from the 65% sequence homology and display significant serologic provirus DNA into viral RNA. The U3 sequence in the long cross-reactivity. terminal repeat contains both a promoter and an enhancer. The human lymphotropic viruses have a marked affin- The enhancer may help confer tissue specificity on viral ity for mature T cells. HTLV-1 is expressed at very low levels expression. The proviral DNA is transcribed by the host in infected individuals. It appears that the viral promoter- enzyme, RNA polymerase II. Full-length transcripts (capped, enhancer sequences in the long terminal repeat may be polyadenylated) serve as genomic RNA for encapsidation in responsive to signals associated with the activation and pro- progeny virions. Some transcripts are spliced, and the subge- liferation of T cells. If so, the replication of the viruses may nomic messenger RNAs (mRNAs) are translated to produce be linked to the replication of the host cells—a strategy that viral precursor proteins that are modified and cleaved to would ensure efficient propagation of the virus. form the final protein products. The human retroviruses are transregulating (see If the virus happens to contain a transforming gene, the Figure 43-2). They carry a gene, tax, whose product alters the oncogene plays no role in replication. This is in marked con- expression of other viral genes. Transactivating regulatory trast to the DNA tumor viruses, in which the transforming genes are believed to be necessary for viral replication in vivo genes are also essential viral replication genes. and may contribute to oncogenesis by also modulating cel- Virus particles assemble and emerge from infected lular genes that regulate cell growth. host cells by budding from plasma membranes. The viral There are several genetic subtypes of HTLV-1, with the protease then cleaves the Gag and Pol proteins from the major ones being subtypes A, B, and C (these do not represent precursor polyprotein, producing a mature infectious distinct serotypes). virion prepared for reverse transcription when the next cell The virus is distributed worldwide, with an estimated is infected. 20 million infected individuals. Clusters of HTLV-associated A salient feature of retroviruses is that they are not disease are found in certain geographic areas (southern cytolytic; that is, they do not kill the cells in which they Japan, Melanesia, the Caribbean, Central and South America, replicate. The exceptions are the lentiviruses, which may and parts of Africa) (Figure 43-5). Although less than 1% of be cytolytic (see Chapter 44). The provirus remains inte- people worldwide have HTLV-1 antibody, up to 5% of the grated within the cellular DNA for the life of the cell. population in endemic areas may be seropositive. Riedel_CH43_p635-p654.indd 643 04/04/19 5:11 PM  644   SECTION IV  Virology A B A A A C E A A C B D A FIGURE 43-5 Subtypes of human T-lymphotropic virus type 1 are geographically distributed in endemic foci. A: Japan, India, the Caribbean, and the Andes; B: Japan and India; C: West Africa and the Caribbean; D: Central Africa; E: Papua New Guinea. (Courtesy of N Mueller.) ATL is poorly responsive to therapy. The 5-year survival rate for patients with this cancer is less than 5%. DNA TUMOR VIRUSES Transmission of HTLV-1 seems to involve cell-associated Fundamental differences exist between the oncogenes of virus. Mother-to-child transmission via breastfeeding is an DNA and RNA tumor viruses. The transforming genes car- important mode. Efficiency of transmission from infected ried by DNA tumor viruses encode functions required for mother to child is estimated at 15–25%. Such early-life infec- viral replication and do not have normal homologs in cells. In tions are associated with the greatest risk of ATL. Blood contrast, retroviruses either carry transduced cellular onco- transfusion is an effective means of transmission, as are shar- genes that have no role in viral replication or they act through ing blood-contaminated needles (drug abusers) and sexual indirect mechanisms. The DNA virus transforming proteins intercourse. complex with normal cell proteins and alter their function. Seroepidemiology has linked infection with HTLV-1 to To understand the mechanism of action of DNA virus trans- a syndrome called HTLV-1-associated myelopathy/tropical forming proteins, it is important to identify the cellular tar- spastic paraparesis (HAM/TSP). The primary clinical feature gets with which they interact. Examples of such interactions is development of progressive weakness of the legs and lower are shown in Table 43-4. body. The patient’s mental faculties remain intact. HAM/TSP is described as being of the same magnitude and importance TABLE 43-4 Examples of DNA Virus Oncoproteins in the tropics as is multiple sclerosis in Western countries. and Cellular Protein Interactionsa Other HTLV-1-associated diseases include uveitis and infec- Viral tive dermatitis. Virus Oncoproteins Cellular Targets Polyomavirus SV40 Large T antigen p53, pRb B. Human Immunodeficiency Viruses Small t antigen PP2A A group of human retroviruses has been established as the cause of acquired immune deficiency syndrome (AIDS) (see Human E6 p53, DLG, MAGI-1, Chapter 44). The HIV are cytolytic and nontransforming and papillomavirus MUPP1 are classified as lentiviruses. However, AIDS patients are at E7 pRb elevated risk of several types of cancer because of the immune Bovine E5 PDGFβ receptor suppression associated with HIV infection. These cancers papillomavirus include cervical cancer, Kaposi sarcoma, lymphomas, head Adenovirus E1A pRb and neck cancer, liver cancer, and oral cancer. E1B-55K p53 Adenovirus 9 E4ORF1 DLG, MAGI-1, MUPP1 C. Other Herpesvirus EBV LMP1 TRAFs The simian foamy viruses from the Spumavirus genus are highly prevalent in captive nonhuman primates. Humans EBV, Epstein-Barr virus; p53, product of p53 gene; PDGF, platelet-derived growth factor; PP2A, protein phosphatase 2A; pRb, retinoblastoma gene product; TRAF, occupationally exposed to the primates can be infected with tumor necrosis factor receptor-associated factor. foamy viruses, but these infections have not resulted in any a DLG, MAGI-1, and MUPP1, members of a family of cellular proteins that contain recognized disease. PDZ domains. Riedel_CH43_p635-p654.indd 644 04/04/19 5:11 PM  CHAPTER 43 Human Cancer Viruses   645 HEPATITIS B VIRUS TABLE 43-5 Important Properties of Polyomavirusesa Hepatitis B virus (see Chapter 35), a member of the Virion: Icosahedral, 45 nm in diameter Hepadnaviridae family, is characterized by 42-nm spherical enveloped virions with a circular genome of double-stranded Composition: DNA (10%), protein (90%) DNA (3.2 kbp). In addition to causing hepatitis, hepatitis B Genome: Double-stranded DNA, circular, 5 kbp virus is a risk factor in the development of liver cancer Proteins: Three structural proteins; cellular histones condense DNA in humans. Epidemiologic and laboratory studies have in virion proved persistent infection with hepatitis B virus to be an important cause of chronic liver disease and the develop- Envelope: None ment of hepatocellular carcinoma. Hepatitis B virus infec- Replication: Nucleus tions occurring in adults are usually resolved, but primary Outstanding characteristics: infections in neonates and young children tend to become chronic in up to 90% of cases. It is these persistent hepati- Stimulate cell DNA synthesis tis B virus infections established early in life that carry the Viral oncoproteins interact with cellular tumor suppressor proteins highest risk of hepatocellular carcinoma later in life. The Important model tumor viruses mechanism of oncogenesis remains obscure. Persistent viral Human viruses can cause human neurologic and renal disease infection leads to necrosis, inflammation, and liver regen- eration that, over time, results in cirrhosis; hepatocellular May cause human cancer carcinoma usually arises out of this background. The hepa- a Formerly classified in Papovaviridae family. titis B virus transactivator protein, X protein, is a potential viral oncoprotein. A dietary carcinogen, aflatoxin, may be a cofactor for hepatocellular carcinoma, especially in Africa symmetry (Figure 43-6). Cellular histones are used to con- and China. dense viral DNA inside virus particles. There are over 250 million people living with chronic Polyomaviruses are simple DNA-containing viruses hepatitis B infection worldwide, with more than 800,000 that possess a limited amount of genetic information (six or deaths annually due to cirrhosis and hepatocellular car- seven genes). Multiple species have been identified, including cinoma. The advent of an effective hepatitis B vaccine for the tumor virus SV40 and others known to infect humans the prevention of primary infection raised the possibility (BK, JC, KI, WU, MCV, HPyV6, HPyV7, HPyV10, and TSV). of prevention of hepatocellular carcinoma, particularly in Many species of mammals and some birds have been found to areas of the world where infection with hepatitis B virus carry their own species of polyomavirus. is hyperendemic (eg, Africa, China, and Southeast Asia). Twenty years after the initiation of a universal hepatitis B vaccination program in Taiwan, chronic hepatitis B virus infection rates and liver cancer incidence rates were mark- edly reduced. Woodchucks are an excellent model for hepatitis B virus infections of humans. A similar virus, woodchuck hepatitis virus, establishes chronic infections in both newborn and adult woodchucks, many of which develop hepatocellular carcinomas within a 3-year period. POLYOMAVIRUSES Important properties of polyomaviruses are listed in Table 43-5. Classification The Polyomaviridae family contains a single genus desig- nated Polyomavirus, formerly part of the Papovaviridae fam- ily (which no longer exists). Polyomaviruses are small viruses (diameter 45 nm) that possess a circular genome of double- FIGURE 43-6 Polyomavirus SV40. Purified preparation stranded DNA (5 kbp; molecular weight 3 × 106) enclosed negatively stained with phosphotungstate (150,000×). (Courtesy of within a nonenveloped capsid exhibiting icosahedral S McGregor and H Mayor.) Riedel_CH43_p635-p654.indd 645 04/04/19 5:11 PM  646   SECTION IV  Virology Polyomavirus Replication properties of pRb and p53, allowing cells to enter S phase so that viral DNA may be replicated. Likewise, functional inac- The polyomavirus genome contains “early” and “late” tivation of the cellular proteins by T antigen binding is cen- regions (Figure 43-7). The early region is expressed soon after tral to the virus-mediated transformation process. As p53 infection of cells; it contains genes that code for early proteins— senses DNA damage and either blocks cell cycle progression for example, the SV40 large tumor (T) antigen, which is or initiates apoptosis, abolishing its function would lead to necessary for the replication of viral DNA in permissive cells, accumulation of T antigen-expressing cells with genomic and the small tumor (t) antigen. The murine polyoma virus mutations that might promote tumorigenic growth. genome encodes three early proteins (small, middle, and large T antigens). One or two of the T antigens are the only viral gene products required for transformation of cells. Pathogenesis and Pathology Usually, the transforming proteins must be continuously syn- The human polyomaviruses BK and JC are widely distrib- thesized for cells to stay transformed. The late region consists uted in human populations, as evidenced by the presence of genes that code for the synthesis of coat protein; they have of specific antibody in 70–80% of adult sera. Infection no role in transformation and usually are not expressed in usually occurs during early childhood. Both viruses may transformed cells. persist in the kidneys and lymphoid tissues of healthy indi- SV40 T antigen interacts with the cellular tumor sup- viduals after primary infection and may reactivate when the pressor gene products, p53 and pRb family members (see host’s immune response is impaired, for example, by renal Table 43-4). Interactions of T antigen with the cellular proteins transplantation, during pregnancy, or with increasing age. are important in the replicative cycle of the virus. This com- Viral reactivation and shedding in urine are asymptom- plex formation functionally inactivates the growth-inhibitory atic in immunocompetent persons. The viruses are most commonly isolated from immunocompromised patients, in whom disease may occur. BK virus causes hemorrhagic VP1 cystitis in bone marrow transplant recipients. It is the cause 99 of polyomavirus-associated nephropathy in renal trans- 14 1618 plant recipients, a serious disease that occurs in up to 5% P3 1 0 of recipients and results in graft failure in up to 50% of 2591 those affected patients. JC virus is the cause of progressive V.9.1 2693 multifocal leukoencephalopathy, a fatal brain disease that 2 EcoRI VP 916.2 occurs in some immunocompromised persons, especially.8 those with depressed cell-mediated immunity resulting Late 52 0 SV40 from immunosuppressive therapies or infection by HIV. 562 rly 0.3 Progressive multifocal leukoencephalopathy affects about LP1 Ea Ori.7 43 5% of AIDS patients. BK and JC viruses are antigenically 52 516 335 distinct, but both encode a T antigen that is related to SV40 516 3.4 -ag m.6 T antigen. These human viruses can transform rodent cells S 3 al eT lT.5 -ag and induce tumors in newborn hamsters. JC virus has been rg La 4639 associated with human brain tumors, but an etiologic role is 49 not yet established. 18 KI and WU viruses were discovered in 2007 in naso- 4571 pharyngeal aspirates from children with respiratory infec- FIGURE 43-7 Genetic map of the polyomavirus SV40. The thick tions. Merkel cell polyomavirus was identified in 2008 in circle represents the circular SV40 DNA genome. The unique EcoRI Merkel cell carcinomas, rare skin tumors of neuroendocrine site is shown at map unit 0/1. Nucleotide numbers begin and end origin. Seroprevalence studies suggest that KI, WU, and at the origin (Ori) of viral DNA replication (0/5243). Boxed arrows Merkel cell virus infections are common and widespread indicate the open reading frames that encode the viral proteins. and occur in childhood. HPyV6, HPyV7, and HPyV10 Arrowheads point in the direction of transcription; the beginning appear to be constituents of human skin. Trichodysplasia and end of each open reading frame are indicated by nucleotide spinulosa–associated polyomavirus (TSV) was discovered numbers. Various shadings depict different reading frames used in proliferative skin lesions, HPyV9 was found in the blood for different viral polypeptides. Note that large T antigen (T-ag) of immunosuppressed patients, and HPyV12 was found is coded by two noncontiguous segments on the genome. The in liver tissue. Other polyomaviruses have been found in genome is divided into “early” and “late” regions that are expressed before and after the onset of viral DNA replication, respectively. human stool, including MWPyV and STL polyomavirus. Only the early region is expressed in transformed cells. (Reproduced Because of their recent discoveries, information on disease with permission from Butel JS, Jarvis DL: The plasma-membrane- associations is limited. associated form of SV40 large tumor antigen: Biochemical and Merkel cell virus appears to be etiologically important biological properties. Biochim Biophys Acta 1986;865:171.) in a large fraction of Merkel cell carcinomas. In many of the Riedel_CH43_p635-p654.indd 646 04/04/19 5:11 PM  CHAPTER 43 Human Cancer Viruses   647 tumors characterized, Merkel cell virus DNA is clonally inte- Classification grated in tumor cells, oncogene expression is required for cell The Papillomaviridae family is a very large virus family cur- growth, and the integrated viral genomes have mutations in rently divided into 16 genera, of which five contain members the T antigen gene that prevent viral DNA replication. that infect humans (Alpha-, Beta-, Gamma-, Mupa-, and SV40 replicates in certain types of monkey and human Nupapillomavirus). The papillomaviruses are former mem- cells; it is highly tumorigenic in experimentally inoculated bers of the Papovaviridae family. Although papillomaviruses hamsters and in transgenic mice and can transform many and polyomaviruses share similarities in morphology, nucleic types of cells in culture. Tumor induction in the natural acid composition, and transforming capabilities, differences host—the rhesus monkey—is rarely observed. SV40 may in genome organization and biology led to their separa- cause a progressive multifocal leukoencephalopathy-like dis- tion into distinct virus families. The papillomaviruses are ease in rhesus monkeys. slightly larger in diameter (55 nm) than the polyomaviruses SV40 contaminated early lots of live and killed poliovirus (45 nm) and contain a larger genome (8 kbp vs 5 kbp). The vaccines that had been grown in monkey cells unknowingly organization of the papillomavirus genome is more complex infected with SV40. Millions of people worldwide received (Figure 43-8). There is widespread diversity among papillo- such SV40-contaminated vaccines between 1955 and 1963. maviruses. Because neutralization tests cannot be done since SV40 is detected in humans today, including in individuals there is no in vitro infectivity assay, papillomavirus isolates too young to have been exposed via vaccination. Evidence are classified using molecular criteria. Virus “types” are at suggests that it (and other polyomaviruses) may be trans- least 10% dissimilar in the sequence of their L1 genes. Almost mitted by the fecal–oral route in humans. The prevalence of 200 distinct HPV types have been recovered. SV40 infections in humans appears to be low. SV40 DNA has been detected in selected types of human tumors, including brain tumors, mesotheliomas, bone Papillomavirus Replication tumors, and lymphomas. The role SV40 may be playing in Papillomaviruses are highly tropic for epithelial cells of the formation of human cancers is unknown. skin and mucous membranes. Viral nucleic acid can be found The host range for polyomaviruses is often highly in basal stem cells, but late gene expression (capsid proteins) restricted. Usually, a single species can be infected and only is restricted to the uppermost layer of differentiated kerati- certain cell types within that species. Exceptions are the pri- nocytes (Figure 43-9). Stages in the viral replicative cycle are mate polyomaviruses SV40 and BK virus; SV40 can also infect dependent on specific factors that are present in sequential humans and human cells, and BK virus can infect some mon- differentiated states of epithelial cells. This strong depen- keys and monkey cells. dence of viral replication on the differentiated state of the host cell is responsible for the difficulties in propagating pap- illomaviruses in vitro. PAPILLOMAVIRUSES Important properties of papillomaviruses are listed in Pathogenesis and Pathology Table 43-6. Transmission of viral infections occurs by close contact. Viral particles are released from the surface of papilloma- TABLE 43-6 Important Properties of tous lesions. It is likely that microabrasions allow infection of Papillomavirusesa proliferating basal layer cells at other sites or within different hosts. Virion: Icosahedral, 55 nm in diameter Papillomaviruses cause infections at cutaneous and Composition: DNA (10%), protein (90%) mucosal sites, sometimes leading to the development of dif- Genome: Double-stranded DNA, circular, 8 kbp ferent kinds of warts, including skin warts, plantar warts, flat warts, anogenital warts, laryngeal papillomas, and sev- Proteins: Two structural proteins; cellular histones condense DNA in virion eral cancers, including those of the cervix, vulva, penis and anus, and a subset of head and neck cancers (Table 43-7). The Envelope: None multiple types of HPV isolates are preferentially associated Replication: Nucleus with certain clinical lesions, though distribution patterns are Outstanding characteristics: not absolute. HPV genital infections are sexually transmitted and represent the most common sexually transmitted disease Stimulate cell DNA synthesis in the United States. Cervical cancer is the second most fre- Restricted host range and tissue tropism quent cancer in women worldwide (about 500,000 new cases Significant cause of human cancer, especially cervical cancer annually) and is a major cause of cancer deaths in developing countries. Viral oncoproteins interact with cellular tumor suppressor proteins Based on the relative occurrence of viral DNA in cer- a Formerly classified in Papovaviridae family. tain cancers, HPV types 16 and 18 are considered to be Riedel_CH43_p635-p654.indd 647 04/04/19 5:11 PM  648   SECTION IV  Virology Episomal Enhancer Functions Copy no. DNA replication trans-activate Control region Transform Modulate Repress Transform Minor capsid Major capsid Open reading frames 1 E1 E5b L2 2 E7 E2 E5a L1 URR 3 E6 E4 0 1 2 3 4 5 6 7 7.902 Kilobase FIGURE 43-8 Map of the human papillomavirus genome (HPV-6, 7902 base pairs). The papillomavirus genome is circular but is shown linearized in the upstream regulatory region (URR). The URR contains the origin of replication and enhancer and promoter sequences. Early (E1–E7) and late (L1, L2) open reading frames and their functions are shown. All the open reading frames are on the same strand of viral DNA. Biologic functions are extrapolated from studies with the bovine papillomavirus. The organization of the papillomavirus genome is much more complex than that of a typical polyomavirus (compare with Figure 43-7). (Reproduced with permission from Broker TR: Structure and genetic expression of papillomaviruses. Obstet Gynecol Clin North Am 1987;14:329. Copyright Elsevier.) high cancer risk; about 16 other less common types are progression to malignancy; however, persistent infection somewhat less frequently associated with neoplasms but with a high-risk HPV is a necessary component to the pro- are also considered high risk. Many HPV types are con- cess (Figure 43-10). sidered benign. Integrated copies of viral DNA are usually present in cervical cancer cells, though HPV DNA is generally not Clinical Findings and Epidemiology integrated (episomal) in noncancerous cells or premalignant An estimated 660 million people worldwide have HPV lesions. Skin carcinomas appear to harbor HPV genomes in genital infections, the most common viral infection of the an episomal state. Viral early proteins E6 and E7 are synthe- reproductive tract. An estimated 20 million Americans are sized in cancer tissue. These are HPV-transforming proteins, infected, with about 6 million new infections occurring able to complex with Rb and p53 and other cellular proteins annually in the United States. The peak incidence of HPV (see Table 43-4). infections occurs in adolescents and young adults younger The behavior of HPV lesions is influenced by immu- than 25 years. nologic factors. Cell-mediated immunity is important. The HPVs are accepted as the cause of anogenital cancers. majority of HPV infections are cleared and become undetect- Over 99% of cervical cancer cases and over 80% of anal can- able within 2–3 years. Development of HPV-associated carci- cer cases are linked to genital infections with HPVs. Papil- nomas requires persistent infection. lomaviruses illustrate the concept that natural viral strains Cervical cancer develops slowly, taking years to may differ in oncogenic potential. Although many different decades. It is thought that multiple factors are involved in HPV types cause genital infections, HPV-16 or HPV-18 is Epidermal cell differentiation Papilloma Viral life cycle pathway Capsid proteins Stratum corneum Virus particles (horny layer) Stratum granulosum (granular layer) Replicating viral DNA Stratum spinosum Expression of (prickle cells) early genes Mitosis Viral DNA Basal cell (low copy number) FIGURE 43-9 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 on the left. Events in the virus life cycle are noted on the right. Late events in viral replication (capsid protein synthesis and virion morphogenesis) occur only in terminally differentiated cells. (Reproduced with permission from Butel JS: Papovaviruses. In Baron S [editor]. Medical Microbiology, 3rd ed. Churchill Livingstone, 1991.) Riedel_CH43_p635-p654.indd 648 04/04/19 5:11 PM  CHAPTER 43 Human Cancer Viruses   649 TABLE 43-7 Examples of Association of Human Papillomaviruse