Papovaviruses

BK Virus, JC Virus, and Simian Virus 40

BK virus (BKV), JC virus (JCV), and simian virus 40 (SV-40) belong to the family of Papovaviridae. The three viruses are similar in structural and functional properties.64,65 Nucleotide sequence homology of the three viruses is 68% to 72%, and protein sequence homology is 76% to 90% in different regions of the viral genomes.64 Primary infection by BKV and JCV occurs in childhood and is usually unapparent. During primary infection, the virus spreads by viremia to several organs and establishes a latent infection in the kidneys. Reactivation from latency can be induced by immunologic impairment. BKV and JCV are ubiquitous in the human population worldwide, and seroprevalence in adults is 80% to 100%. Both viruses are probably transmitted by the respiratory and the orofecal route.4,66,67 BKV and JCV cause posttransplantation interstitial nephritis in renal transplant recipients and BKV causes hemorrhagic cystitis in bone marrow transplant patients.4,64-66 JCV is the etiologic agent of progressive mul-tifocal leukoencephalopathy, a severe degenerative neurologic disease affecting immunosuppressed individuals.64,65 SV-40, which is a monkey virus, was introduced only recently into the human population when polio vaccines, produced in SV-40-contaminated monkey kidney cell cultures, were massively administered to millions of individuals between 1955 and 1963.68 Soon it was shown that people vaccinated with SV-40-contaminated polio vaccines shed infectious SV-40 in stools for at least 5 weeks after vaccination.69 This observation suggested that SV-40 could be transmitted from recipi ents of contaminated polio vaccines to contacts by the orofe-cal route and could spread in humans by horizontal infection. This hypothesis is supported by some experimental results. First, SV-40 DNA sequences have been detected in normal and neoplastic tissues of persons too young (1 to 30 years) to have been vaccinated with SV-40-contaminated polio vac-cines.3,70-74 Second, SV-40 sequences have been found in blood specimens of neoplastic and healthy individuals72,74,75-79 and SV-40 virions were detected in urine and sewage samples,68,80 suggesting that the hematalogic and orofecal routes of transmission might be responsible for SV-40 horizontal infection in humans. An alternative or additional hypothesis is that some polio vaccines continued to be contaminated by SV-40 after 1963.81 Third, infectious SV-40 was rescued by transfec-tion of monkey cells with the DNA of an SV-40-positive human choroid plexus carcinoma in an individual too young to have received a contaminated vaccine.82 Finally, antibodies to SV-40 capsid antigens were found in sera of children and of both normal and HIV-1-infected adults.83-86

The early region of the BKV, JCV, and SV-40 genomes, which is expressed in the initial phase of the replicative cycle, encodes the two viral oncoproteins: the large T antigen (Tag) and the small t antigen (tag). The Tag displays multiple functions that alter the normal physiologic metabolism of cells, ultimately leading to immortalization and neoplastic trans-formation.64,65,87-89 An important property of Tag in relation to transformation and oncogenicity is its ability to bind and block the functions of the tumor suppressors p53 and the pRb family proteins (p105 Rb1, p107, and p130 Rb2).88-91 Poly-omavirus Tag induces chromosomal damage in human cells characterized by numerical and structural chromosomal aberrations such as DNA gaps, breaks, dicentric and ring chromosomes, deletions, duplications, and translocations.92-95 The molecular mechanism of the clastogenic effect of Tag may reside in its ability to bind topoisomerase I96 and in its heli-case activity,97 which could induce chromosome damage when Tag promotes the unwinding of the two strands of cellular DNA. Moreover, Tag inhibition of p53-induced apopto-sis allows DNA-damaged cells to survive, increasing their probability of becoming transformed and acquiring immor-tality.89 Small tag98 cooperates with large Tag in transformation by reducing serum dependence of transformed cells and binds protein phosphatase 2A (PP-2A).99 PP-2A is a serine/threonine phosphatase that regulates the phosphoryla-tion signaling activated by protein kinases,100 and it has recently been shown to function as a tumor suppressor gene involved in some lung, colon, and breast carcinomas and melanoma.101,102 In addition, SV-40 small tag is able to enhance transcription of E2F-activated early growth response genes.103

BKV, JCV, and SV-40 transform to neoplastic phenotypes and are highly oncogenic in rodent and human cells.3 The spectrum of experimentally induced tumors is similar but distinct for each of the three viruses.3 BKV, JCV, and SV-40 DNA were detected in human tumors by PCR, and occasionally by Southern hybridization of the whole cell genome, indicating the presence of relatively low amounts of viral sequences. Expression of virus-specific RNA and Tag was often observed in virus-positive tumors. The histotype of the human tumors positive for viral sequences corresponds to that of the tumors induced by the three viruses in experimental animals. BKV has been associated to human brain tumors, tumors of pan creatic islets, osteosarcomas, and tumors of the urinary tract.3'4'64-66'104 BKV DNA sequences were also detected in primary KS and in KS cell lines.105 JCV has been associated with human brain tumors, especially astrocytoma and medul-loblastoma,64,65,106-109 and possibly with colorectal carcinoma.109-112 In colorectal cancers, negative for mutations in the APC gene, JCV Tag activates the Wnt pathway, with consequent constitutive expression of b-catenin,113 which leads to continuous cell proliferation. SV-40 is associated with human mesothelioma, with brain tumors, and possibly with osteosarcoma and non-Hodgkin's B-cell lymphoma.114-117 Human brain tumors can be coinfected by SV-40 and BKV or by SV-40 and JCV,107 suggesting a possible interaction between polyomaviruses in oncogenesis. In three human brain tumors, one of the authors (G.B.B.) detected the simultaneous presence of the DNA sequences of BKV, JCV, and SV-40.4,66 It remains to be demonstrated whether in these tumors the viruses coexist in the same cells. Some studies, however, did not detect SV-40 in human tumors.118 Three independent panels have reviewed the association of SV-40 with human tumors: one organized by the National Cancer Institute,28 one by the Institute of Medicine,119 and one at an international SV-40 mesothelioma consensus conference held at the University of Chicago.120 All three panels concluded that there is compelling evidence that SV-40 is present in some human tumors, especially mesothelioma and brain tumors, and that SV-40 is a potent cocarcinogen.

Because BKV and JCV are ubiquitous in humans,3 their DNA sequences are often detected not only in tumors but also in normal tissues.72,74 The viral load in BKV-, JCV-, and SV-40-positive human tumors is usually low (10-2 to 10-4 genome equivalents per cell), and Tag is expressed only in a fraction of tumor cells.3,75 This is a general characteristic of polyomavirus-induced tumors: for example, only a fraction of tumor cells in SV-40 transgenic tumors is Tag positive. However, BKV, JCV, and SV40 induce chromosome aberra-tions92,95 that can affect the functions of genes important in tumorigenesis.121 Once the genetic damage has been triggered in tumors and chromosomal alterations have reached a threshold, genomic instability ensues122,123 as a result of the functional alteration of DNA repair genes, especially in the presence of Tag-mediated inactivation of cellular p53, which prevents DNA repair or apoptosis of damaged cells. These events lead to accumulation of genetic lesions and to tumor progression.122,123 A similar course of events may occur in some polyomavirus-positive human tumors, where the clas-togenic activity of Tag, similarly to a chemical or physical carcinogen, initiates the tumorigenic process by causing DNA damage, and then becomes dispensable; it may be lost during tumor progression when the accumulation of genetic alterations renders the presence of viral transforming genes unnecessary. Immunoselection may select against persistently polyomavirus-infected cells, whereas genetically mutated cells that have lost the viral genome may have a pro-liferative advantage and become the prevalent population in the tumor. This "hit-and-run" mechanism has been demonstrated in SV-40-mediated transformation of some rodent cells.124,125 In human mesothelial cells, SV-40 Tag activates an autocrine-paracrine loop involving the hepatocyte growth factor (HGF) and its cellular receptor, the oncogene c-met,126 as well as VEGF and its cellular receptor.127,128 It has been suggested that HGF and VEGF, released from SV-40-positive cells, bind their receptors in neighboring SV-40-negative cells, driving them into proliferation and tumorigenesis.126-129

There is strong evidence in support of a causative association between SV40 and mesothelioma, including (1) the ability of SV-40 Tag to bind and inactivate p53 and Rb family proteins in primary human mesotheliomas130,131; (2) the induction of growth arrest and apoptosis in mesothelioma cell lines transfected with antisense DNA to the SV-40 early region gene132; (3) the presence of SV40 in malignant mesothelioma cells and not in nearby stromal cells microdissected from the same slide133; and (4) the activation, in primary human mesothelial cells, of Notch-1, a gene promoting cell-cycle progression and cell proliferation,134 considered a general requirement for the maintenance of the neoplastic phenotype in human cells.135 Also, (5) human mesothelial cells are resistant to SV-40-induced cell lysis and are particularly susceptible to SV-40-mediated transformation126,136 because human mesothelial cells limit SV-40 replication thanks to the endogenous high levels of wild-type p53.136,137 Therefore, SV-40 DNA remains episomal, the viral oncogenes are expressed, cell lysis is limited, and the frequency of transformation is high (1-5 x 10-3 transformed foci in human mesothelial cells compared to 1 x 10-7-1 x 10-8 transformed foci in human fibroblasts).136,137 ( 6) Human mesothelial cells are specifically susceptible to SV-40 infection compared to the human poly-omavirus JCV, which does not infect mesothelial cells, and BKV, which causes mesothelial cell lysis.138 (7) Asbestos, which is the main cause of human mesothelioma, cooperates with SV-40 in transformation of human mesothelial cells,136 suggesting that asbestos and SV-40 are cocarcinogens in the pathogenesis of mesothelioma. (8) SV-40 tumor antigens induce telomerase activity in human mesothelial cells,138 a requirement for cellular immortalization and tumor growth. (9) SV-40 induces promoter methylation and inactivation of the RASSF1A tumor suppressor gene in both SV-40-positive mesothelioma and in SV-40-transformed human mesothelial cells.137 Most of the conflicting arguments concerning the role of SV-40 in human tumors have been extensively discussed in a recent critical review139 that points out the unique features of SV-40 infection in humans and emphasizes the limitations of the conventional studies of descriptive epidemiology which cannot reliably distinguish among infected and noninfected cohorts.119,139

Human Papillomaviruses

Papillomaviruses belong to the family Papovaviridae and are small (55 nm), nonenveloped viruses with a double-stranded circular DNA genome of about 8 kb. Papillomaviruses infect several animal species and are highly species specific and epitheliotropic. The human papillomavirus (HPV) species comprises more than 140 different types, but only a few types are prevalent in human neoplasia.140,141 HPV is associated with both benign and malignant proliferative epithelial lesions affecting the genital organs and skin.142 The mucosal HPV types infect the anogenital tract. Low-risk HPVs, with HPV-6 and HPV-11 as classic representatives, induce benign proliferations such as condylomata acuminata and papillomas that often regress and only rarely progress to malignancy. High-risk HPVs are associated to cervical cancer and other anogenital malignancies, such as vulva, vagina, penis, and anal cancer. Six HPV types, HPV-16, -18, -31, -33, -35, and

-39, are associated with more than 90% of cervical carcinomas.140,141 The cutaneous HPV types are involved in skin warts and in epidermodysplasia verruciformis (EV), a hereditary autosomal recessive disease associated with a state of immunodeficiency and characterized by a great number of skin warts, often disseminated and confluent. In up to half of the affected patients, the warts of EV progress to skin carci-nomas,140-143 usually in sun-exposed sites because of the effect of UV irradiation, a clear example of cooperation in human carcinogenesis between a physical agent and viral infection and genetic predisposition. The HPV types most commonly involved in skin warts and EV lesions are HPV-5, -8, -9, -12, -14, -20, -23, -38, -49, and -75, but the squamous cell carcinomas arising from EV lesions contain mostly HPV-5, -8, -20, -23, and -38.140-143

The role of HPV in human neoplasia involves complex mechanisms.140-144 Of great importance in the pathogenesis of both genital and cutaneous HPV-associated tumors is host immunosuppression, especially loss of cell-mediated immunity. Skin warts and cutaneous squamous cell carcinomas are common in immunosuppressed transplant recipients, and the frequency of condylomata acuminata and cervical cancer is enhanced in HIV-1-infected patients.140,141 Most of the information about the role of HPV in anogenital tumorigenesis has been obtained from studies of cervical cancer.144 While the genome of the low-risk HPV-6 and HPV-11 remains episomal in benign genital papillomas, the DNA of high-risk HPV-16, -18, -31, and -33 becomes integrated into the DNA of the tumor cells in cervical cancer.144,145 Despite frequent loss of much of the viral genome in cervical cancer cells, the regions encoding the early viral proteins E6 and E7 are always maintained and expressed in HPV-positive cervical cancers.140-145 Analysis of the high-risk HPV genomes in a variety of in vitro systems and in primary tumors indicated that the E6 and E7 genes are the primary oncogenes of HPV. HPV cannot be grown in vitro, possibly because virus maturation specifically requires differentiated epidermal cells. However, in vitro studies using retrovirus-mediated gene transfer and other transfection techniques demonstrated that HPV-16 or HPV-18 E6 and E7 genes in combination were able to efficiently immortalize and transform primary human foreskin kera-tinocytes (which resemble the normal in vivo target cells of HPV), whereas E7 alone immortalized genital keratinocytes at a reduced efficiency and E6 alone was ineffective.146-148 HPV-16- and HPV-18-transformed keratinocytes showed aberrant differentiation patterns that made them almost indistinguishable from cells of low-grade cervical intraepithelial neoplasia, a precursor of cervical cancer.146-148 Retrovirus constructs encoding low-risk HPV-6 E7 alone or both HPV-6 E6 and E7 failed to immortalize genital keratinocytes.148

Subsequent molecular analysis of the transforming activities of E6 and E7 oncoproteins has elucidated their role in the pathogenesis of genital cancer. The E6 protein of high-risk HPV types binds the p53 tumor suppressor protein with high affinity and mediates its degradation via the ubiquitin pathway.149,150 The E6 protein also activates telomerase151 and binds E6BP or ERC55, a calcium-binding protein152,153 that may influence keratinocyte differentiation. Moreover, E6 binds paxillin,154 which mediates a variety of signals from the cytoplasmic membrane to focal adhesion molecules and the actin cytoskeleton and binds, and possibly inactivates the hDLG protein,155,156 the human homologue of the Drosophila large tumor suppressor protein. E6 transactivates TATA containing heterologous promoters through a mechanism unrelated to p53 binding.157 The observation that although the E6 proteins encoded by several other papillomaviruses, such as bovine papillomavirus, HPV-1, and HPV-8, do not interact with p53 yet show strong transforming activity,158 emphasizes the biologic relevance of these additional E6 activities.

The E7 oncoprotein binds p105Rb. The affinity of high-risk E7 proteins for pRb is severalfold higher than that of low-risk E7 proteins.145,159 pRb plays an important role in cell-cycle control by coordinating entry of cells from G1 into S phase.89,160 Unphosphorylated pRb binds members of the E2F family of transcription factors89,145,161 in early G1. E2F proteins transcriptionally activate c-myb, c-myc, c-fos, c-jun, cyclin A, and cyclin E genes and other genes involved in DNA replication and stimulation of cell proliferation.89,145 By binding to E2F, pRb inhibits E2F-mediated transcriptional activation and thus blocks cell-cycle progression from G1 to S. In normal cells this block is relieved by phosphorylation of pRb through the action of the cyclin-dependent kinases (CDKs), resulting in the dissociation of the E2F-pRb complex. Free E2F is then able to transactivate its cell-cycle-promoting target genes, triggering progression into S phase.89,145,160,161 The E7 oncopro-tein can disrupt the pRb-mediated control of the cell cycle through at least three different mechanisms, leading to release of E2F and to unregulated activation of E2F target genes: (1) the direct binding of E7 to pRb results in a competitive interference with pRb-E2F complex formation,89,145,162 (2) E7-induced degradation of pRb,145,163 and (3) E7-mediated interference with regulatory pathways upstream of pRb, such as blocking the activity of the p21WAF1 CDK inhibitor.164,165 The interaction with pRb is not the only activity through which E7 can contribute to cell transformation, as the transformation potential of mutant E7 proteins does not necessarily correlate with their ability to bind pRb.166-168 E7 also interacts with the pRb-related proteins p107 and p130,89,145 and it has been found in complexes with the cell-cycle regulatory proteins cyclin A, cyclin E, p21WAF1, and p27KIP1.30 E7-induced alterations of the molecular pathways controlled by these cell-cycle regulatory proteins further contribute to the dysregulation of cell growth. E7 interferes with p21WAF1-mediated regulation of DNA methylation30 and with the p21WAF1-induced DNA replication arrest in cells with DNA damage,30 thus favoring the accumulation of DNA damage.169 E7 has transcriptional modulatory activities and can influence transcription of cellular genes in an E2F-independent fashion by interacting with proteins of the AP1 family of transcription factors170 or with general transcription factors, such as the TATA box binding protein (TBP).171

The functional inactivation of the p53 and pRb family gene products by the oncoproteins of high-risk HPV types substitutes for mutations in these tumor suppressor genes. Indeed, it was shown that primary genital tumors and tumor cell lines infected with HPV do not carry mutations in p53 and Rb genes,172,173 although mutations may subsequently occur during tumor progression toward an invasive and metastatic phenotype. Conversely, p53 mutations are detected only in the rare HPV-negative cervical cancers.174 In contrast to high-risk anogenital HPV infections, cutaneous HPV infections may contribute indirectly and in a less complex way to skin squamous cell carcinoma: the presence of HPV may simply protect cells from apoptosis after genetic damage induced by solar exposure, thus resulting in increased survival of the genetically altered cells.141 Besides their involvement in genital and cutaneous carcinogenesis, HPVs are also linked to head and neck cancers and to esophageal carcinoma.141,143,175 Although the transforming functions of HPV E6 and E7 proteins are important pathogenetic factors in human tumorigenesis, they are probably not sufficient to induce malignancy. In animals, human papillomavirus often cooperates with other carcinogens to cause cancer.144 An outstanding example of the synergism between papillomaviruses and environmental factors is bovine papillomavirus, which induces papillomas and carcinomas of the alimentary tract in cattle in cooperation with dietary carcinogens.176 Some metabolites of the vaginal microbial flora, alcohol, and smoke are considered relevant risk factors for the development of cervical, oropharyngeal, and laryngeal cancers.141,143,175 Sexual hormones may enhance the oncogenic effect of HPV on genital tissues, because the promoter of high-risk HPV types harbors consensus sequences responding to transcriptional activation by estrogens and progesterone.30 Herpes simplex virus infection may cooperate with HPV by promoting DNA mutations in genital tissues.177 Physical carcinogens also have a cooperative role, as shown by transition to malignancy of the EV lesions exposed to UV light140-143 and by the frequent conversion of laryngeal papillomas to carcinomas following X-ray treatment.141

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