This family contains 2 genera of oncogenic DNA viruses: The Family was originally named for its 3 main members:


Polyomaviruses infect a wide variety of vertebrates (12 members now known). Polyomavirus was isolated by Gross in 1953 while he was studying leukaemia in mice and named because it caused solid tumours at multiple sites. The second member of the family, Simian Vacuolating Virus 40 (SV40) was isolated by Sweet and Hilleman in 1960 in primary monkey kidney cells cultures being used to grow Sabin OPV (!). Two human Polyomaviruses were isolated in 1971:
BK Virus (BKV) - from an immunosuppressed kidney transplant patient
JC Virus (JCV) - from a case of progressive multifocal leukoencephalopathy (PML).
Because of the small size of their genomes, their oncogenic properties and the existence of in vitro systems, Polyomaviruses have been used extensively as models for DNA replication.


Polyomaviruses virions are non-enveloped, ~45nm diameter T=7 icosahedral particles. The complete structure of SV40 has been described. There are 3 capsid proteins, VP1-3, which form 72 pentameric capsomers, 60 hexagonally co-ordinated +12 pentamerically co-ordinated (at the vertices):

Computer reconstruction of papovavirus particle

There are 3 capsid proteins, VP1-3, which form 72 pentameric capsomers, 60 hexagonally co-ordinated + 12 pentamerically co-ordinated (at the vertices).
Each virion contains 360 copies of VP1 (i.e. 72 x 5) + 30-60 copies each of VP2 & VP3, i.e. ~1 copy/pentamer. Each copy of VP1 has a sialic acid binding site on the surface & these form the receptor-binding site for the virus; hence the particles have haemagglutinating properties.

VP2/3 have overlapping sequences (see below) - VP2 contains the entire sequence of VP3 at it's C-terminus, +115 aa at the N-terminus. The precise location of VP2/3 is unknown. VP2 is myristylated at its NH2-terminus, which is believed to be important in holding the particle together (c.f. Picornavirus VP4).


Polyomavirus genomes are d/s, circular DNA molecules, ~5kbp in size. The entire nucleotide sequence of all the viruses in the family is known and the architecture of the Polyomavirus genome (i.e. number and arrangement of genes and regulatory signals and systems) has been studied in detail.
Within the particles, the DNA assumes a supercoiled form (like plasmid DNA). Four cellular histones H2A, H2B, H3 and H4 are associated with the DNA.
Polyomavirus genomic organization is designed to pack maximal information (6 genes) into minimal space (5kbp). This paradox is achieved by the use of both strands of the genome DNA and overlapping genes:

The origin of replication is surrounded by non-coding regions which control transcription. VP1 is a encoded by a "dedicated" ORF, but the VP2 and 3 genes overlap so that VP3 is contained within VP2. SV40, BKV and JCV encode a small (60-70aa) protein known as the agnoprotein which enhances assembly of virus particles & cell to cell spread.
Polyomaviruses also encode "T-antigens" - proteins which can be detected by sera from animals bearing polyomavirus-induced tumours:

Protein Size (a.a.):
Virus: Large T: Small T: Middle T:
Polyoma 785 195 421
SV40 708 174 ---
BKV 695 172 ---
JCV 688 172 ---

These proteins have common N-terminal regions but unique COOH-termini derived from alternative splicing patterns.


PyV genomes are d/s, circular DNA molecules, ~5kbp in size. The entire nucleotide sequence of all the viruses in the family is known & the architecture of the PyV genome (i.e. number & arrangement of genes & regulatory signals & systems) has been studied in detail.
Within the particles, the DNA assumes a supercoiled form (like plasmid DNA). Four cellular histones H2A, H2B, H3 & H4 are associated with the DNA.

The genome is functionally divided into 3 regions:

  • Early: Expressed early in virus infection, i.e. BEFORE genome replication. Expression of early genes continues during the late stage of infection. Encodes non-structural proteins (i.e. not present in virus particle).
  • Late: Expressed later in virus infection, i.e. DURING & AFTER genome replication. Encodes structural proteins (i.e. present in virus particle).
  • Regulatory region: Contains transcriptional promoters & enhancers plus the unique origin of DNA replication.


    SV40 receptor appears to be MHC class I antigen(s).
    Receptors for PyV are not known, but appear to contain sialic acid (haemagglutination) & be widespread in many tissue/species.
    VP1 (only(?) external protein on virus capsid) responsible for receptor binding (anti-VP1 Abs block binding).


    VP2/3 are myristylated & believed to interact with cellular membranes to facilitate entry.
    Virions are taken up by endocytosis & is transported to the nucleus by interaction of endocytic vacuoles with the cytoskeleton.


    Virus particles enter by the nuclear pores & uncoating occurs inside the nucleus.
    The rest of the replication cycle occurs in the nucleus. VP2/3 mutants defective in uncoating, therefore these proteins are involved in the process, although the details are unknown.

    Gene Expression:

    Inside the nucleus, the virus mini-chromosome (genome-histone complex) is transcribed by host cell RNA polymerase II to produce early mRNAs.
    Because of the relative simplicity of the genome, PyV are heavily dependent on the cell for transcription & genome replication. However, the genome contains cis-acting regulatory signals (surrounding the origin of replication) which direct transcription, & trans-regulatory proteins (the T-antigens) which direct transcription & replication. Alternative splicing produces 2 (or 3) species of early mRNA/T-antigen:
    large-T & small-T (plus middle-T in murine polyomavirus - a membrane protein found in the plasma membrane, important in cell transformation).
    Transcription from the early region promoter is autoregulated by binding of large-T antigen to the regulatory region of the genome:

    The early gene promoter contains strong enhancer elements which cause it to be active in newly infected cells. The early region proteins are the T-antigens.
    Small T-antigen is not essential for virus replication, but indirectly (i.e. interacts with cellular proteins but does not bind directly to virus genome) enhances transcription from the late promoter.
    As the concentration of large T-antigen builds up in the nucleus, transcription of the early genes is repressed by direct binding of the protein to the origin region of the virus genome, preventing transcription from the early promoter and causing the switch to the late phase of infection. After DNA replication has occurred, transcription of the late genes occurs from the late promoter and results in the synthesis of the structural proteins, VP1, VP2 and VP3.
    The SV40 late promoter is a very strong promoter & is activated by binding of large T-antigen to the 72bp repeats upstream of the transcription start site.
    Therefore, the role of the SV40 T-antigen in controlling the transcription of the genome is comparable to that of a 'switch'.

    Genome Replication:

    Large T-antigen has a complex action & binds to various cellular proteins:

    SV40 DNA replication is initiated by binding of large T-antigen to the origin region of the genome. The function of T-antigen is controlled by phosphorylation, which decreases the ability of the protein to bind to the SV40 origin.
    The SV40 genome is very small and does not encode all the information necessary for DNA replication. Therefore, it is essential for the host cell to enter S phase, when cell DNA and the virus genome are replicated together.
    Protein:protein interactions between T-antigen and DNA polymerase-alpha directly stimulate replication of the virus genome. Inactivation of tumour suppressor proteins bound to T-antigen causes G1-arrested cells to enter S phase, promoting DNA replication.
    Therefore, in addition to increasing transcription, another function of T-antigen is to alter the cellular environment to permit virus genome replication.


    Virus proteins contain 'nuclear localization signals' which results in their accumulation in the nucleus, where they migrate after being synthesized in the cytoplasm.
    Assembly occurs in the nucleus. Since the structure of the virus is relatively simple, assembly & maturation of the particle are simultaneous.


    Some virus particles are exported to the cell surface in cytoplasmic vacuoles. The remaining virus is released when the cell lyses (SV40!). Mechanism of cell injury is not clear, but is not a surprise due to the severe interference with normal cellular metabolism & growth that these viruses cause.
    The complete replication cycle takes 48-72h (depending on multiplicity of infection).


    Infection of cells by PyV can result in two outcomes: The outcome appears to be determined primarily by the cell type infected.
    However, after infection, some (unknown) determinant in the intracellular environment (rather than the receptor-V.A.P. interaction) determines the outcome of the infection:

    Transformation is a rare and accidental consequence of the sequestration of tumour suppressor proteins. Inactivation of tumour suppressor proteins bound to T-antigen causes G1-arrested cells to enter S phase and divide and this is the mechanism which results in transformation. However, the frequency with which abortively infected cells are transformed is low (about 1x10-5).

    Therefore, T-antigen:

  • Alters the cellular environment, affecting the cell cycle & DNA replication, enhancing virus replication (simple genomes!)
  • Accidentally may result in cellular transformation
  • Viral DNA replication is initiated by binding of large T-antigen to the origin, replication then proceeds bidirectionally from this point - IMPORTANT MODEL FOR CELLULAR DNA REPLICATION / ONCOGENESIS.

    There is conflicting evidence about the pathogenic potential of Polyomaviruses. Between 1955 and 1963, millions of Americans were exposed to SV40 in Sabin OPV. By 1961 between 80-90% of all U.S. children and adolescents under the age of 20 had been injected. There is no evidence that this had any ill effects. Alternatively, 2 viruses commonly infect man and have been associated with disease.

    Site of primary infection is not known, but may be the respiratory tract. The implications of this are that the vast majority of primary infections with these viruses are asymptomatic. However, both viruses are oncogenic when inoculated into newborn hamsters. Once infected, the viruses persist (for life?) and disease appears to be associated with reactivation rather than primary infection. Pregnancy is known to reactivate Polyomaviruses infections, but without any known pathologic consequence.

    JC Virus

    Associated with progressive multifocal leukoencephalopathy (PML). This is a rare disease, involving plaques of demyelination/inflammation in the CNS. Oligodendrocytes from these lesions (responsible for the synthesis and maintenance of the myelin sheath around neurons) are productively infected with JCV. The disease is seen in two main groups of people: BK Virus: Primary infection is associated with a mild respiratory illness in children. The virus has also been isolated from various human tumours, but a cause and effect relationship has not been demonstrated.

    Search MEDLINE for the latest publications on polyomaviruses:


    The viral nature of human warts was first identified in 1907; the first Papillomavirus was isolated from rabbits by Richard Shope in 1933. In spite of this early start, human Papillomaviruses (HPV) remained largely unstudied until the advent of molecular virology (cloning) in the 1970s. This is because to date, no HPV grows in vitro. Much of our knowledge comes from Bovine Papillomavirus (BPV) for which animal host systems exist.


    Papillomaviruses are small, non-enveloped icosahedral particles ~52-55nm diameter. There are 72 capsomers (60 hexameric + 12 pentameric) arranged on a T = 7 lattice. Apart from the larger size, these appear very similar to Polyomaviruses particles (N.B. no sequence relatedness). There are 2 capsid proteins, 1 major (encoded by the L1 gene) and 1 minor (L2).
    To view a negatively-stained electron micrograph of papillomavirus particles, click here.


    The Papillomavirus genome consists of circular, d/s DNA ~8kbp in size, associated with cellular histones to form a chromatin-like substance. At least 12 different HPV genomes have been sequenced, and the genetic organization is similar to that shown above.


    Individual isolates are highly species specific. All are tropic for squamous epithelial cells (receptors unknown). The virus infects the basal cells of the dermal layer, and early gene expression can be detected in these cells (in situ hybridization). However, late gene expression, expression of structural proteins and vegetative DNA synthesis is restricted to terminally differentiated cells of the epidermis which implies a link between cellular differentiation and viral gene expression.

    Gene: Function:
    E1 Initiation of DNA replication (helicase)
    E2 Transcriptional regulation/DNA replication
    E3 ???
    E4 Late NS protein; Disrupts cytoskeleton?
    E5 Transforming protein, interacts with growth factor receptors, e.g. PDGF
    E6 Transforming protein, binds to p53 leading to degradation
    E7 Transforming protein, binds to pRB
    E8 ???
    L1 Major capsid protein
    L2 Minor capsid protein

    Expression of the Papillomavirus genome is complex because there are:

    Transcription has been studied in detail by transfection of cloned Papillomavirus DNA into cells. Only one strand of the genome is transcribed. Two classes of proteins are produced:
    Early Proteins: Non-structural regulatory proteins, including trans-acting transcriptional regulators (E2, E7).
    Late Proteins: The structural proteins L1 and L2.
    Transformation: Is complex! Depends on the early gene products. The transforming proteins appear to vary from one virus type to another. There is still some confusion about the function/mechanism of the transforming proteins. The general principle appears to be that two (or more) early proteins co-operate to give a transforming phenotype. Although some viruses can transform cells on their own (e.g. BPV-1), others also appear to require co-operation with an activated cellular oncogene (e.g. HPV-16/ras). More confusingly, in most cases, all or part of the Papillomavirus genome including the putative "transforming genes" is maintained in the tumour cells, whereas in other cases (e.g BPV-4), the virus DNA may be lost after transformation - a "hit-and-run" mechanism.

    In HPVs:

    Genome Replication:
    The genome is replicated as a multicopy nuclear plasmid (episome). Two mechanisms are involved in genome replication:

    1. Plasmid Replication - occurs in cells in the lower levels of the dermis. Initially, the virus DNA is amplified to 50-400 copies/diploid genome. After this, it replicates once per cell division, the copy number/cell remaining constant. The E1 protein is involved in this phase of replication.
    2. Vegetative Replication - occurs in terminally differentiated cells in the epidermis. In terminally differentiated cells (or growth-arrested cells in culture) control of copy number appears to be lost and the DNA is amplified up to very high copy numbers (000's copies/cell).
    3. Virus is shed from epidermal cells when these are sloughed off and is transmitted by direct contact (esp. genital warts) and indirect contact.


    These viruses are widespread in nature and infect birds and mammals. The usual outcome of infection is the formation of a benign outgrowth of cells, a wart or papilloma. These may occur almost anywhere in or on the body. Skin warts are divided into flat warts (superficial) and plantar warts (deeper). Genital warts (condylomas) occur in the genital tract and are transmitted by sexual intercourse. Warts can be treated by topical application of caustic substances or freezing, but surgical removal is more reliable, and is required for internal warts e.g. laryngeal. Warts may persist for many years, but may regress spontaneously due to a CTL response. There may be some enhanced risk of skin warts exposed to U.V. light developing into invasive squamous cell carcinoma (very rare).
    However, there is also considerable interest in Papillomaviruses as a cause of cancer, particularly in recent years the possible association between HPV and cervical carcinoma. At least 58 different HPV have been identified using molecular techniques. In the last few years, a number of types have been suggested to be associated with particular tumours:

    Cancer: Predominant types: Co-factors:
    Skin carcinomas HPV-5, 8 U.V., genetic?
    Lower genital tract cancers HPV-16, 18, 31, 33 ???
    Malignant transformation of respiratory papillomas HPV-6, 11 X-rays

    However, these associations are far from certain at the present time:

    Prevalence of Human Papillomavirus in Cervical Cancer: A Worldwide Perspective

    [J Natl Cancer Inst 87:796-802, 1995]

    F. Xavier Bosch, M. Michele Manos, Nubia Muñoz, Mark Sherman, Angela M. Jansen, Julian Peto, Mark H. Schiffman, Victor Moreno, Robert Kurman, Keerti V. Shah, International Biological Study on Cervical Cancer (IBSCC) Study Group

    Background: Epidemiologic studies have shown that the association of genital human papillomavirus (HPV) with cervical cancer is strong, independent of other risk factors, and consistent in several countries. There are more than 20 different cancer-associated HPV types, but little is known about their geographic variation.
    Purpose: Our aim was to determine whether the association between HPV infection and cervical cancer is consistent worldwide and to investigate geographic variation in the distribution of HPV types.
    Methods: More than 1,000 specimens from sequential patients with invasive cervical cancer were collected and stored frozen at 32 hospitals in 22 countries. Slides from all patients were submitted for central histologic review to confirm the diagnosis and to assess histologic characteristics. We used polymerase chain reaction-based assays capable of detecting more than 25 different HPV types. A generalized linear Poisson model was fitted to the data on viral type and geographic region to assess geographic heterogeneity.
    Results: HPV DNA was detected in 93% of the tumors, with no significant variation in HPV positivity among countries. HPV 16 was present in 50% of the specimens, HPV 18 in 14%, HPV 45 in 8%, and HPV 31 in 5%. HPV 16 was the predominant type in all countries except Indonesia, where HPV 18 was more common. There was significant geographic variation in the prevalence of some less common virus types. A clustering of HPV 45 was apparent in western Africa, while HPV 39 and HPV 59 were almost entirely confined to Central and South America. In squamous cell tumors, HPV 16 predominated (51% of such specimens), but HPV 18 predominated in adenocarcinomas (56% of such tumors) and adenosquamous tumors (39% of such tumors).
    Conclusions: Our results confirm the role of genital HPVs, which are transmitted sexually, as the central etiologic factor in cervical cancer worldwide. They also suggest that most genital HPVs are associated with cancer, at least occasionally. Implication: The demonstration that more than 20 different genital HPV types are associated with cervical cancer has important implications for cervical cancer-prevention strategies that include the development of vaccines targeted to genital HPVs.

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