Generalities
 

    The papillomaviruses are part of the PAPOVAVIRIDAE family of DNA tumor viruses. First discovered in the early 40’s, the papillomaviruses were linked to the appearance and persistance of benign skin growths (warts) in the cottontail rabbit. After some time, the warts went on to malignant tranformation suggesting that papillomaviruses may be associated to cancer. Since then, other papillomaviruses were described as associated to benign warts in other species including humans. Papillomaviruses gained notoriety in the early 80’s when it was discovered that some types of  human papillomaviruses (HPV) were associated to cervical cancer, one of the most widely spread forms of cancer world-wide.
     Papillomavirus genome is circular covalently closed double stranded DNA of about 8 kbp. Unlike other papovaviruses (i.e. polyomavirus or SV40), all papillomaviruses genes are coded in one of the two DNA strands, utilizing the three forward reading frames and alternative splicing for the individual expression of each gene. As a consequence, papillomavirus expression  is characterized by a large array of mRNAs coding for different genes. In animal papillomaviruses (i.e. BPV-1, CRPV) early and late transcripts originate from several promoters, whereas in HPV transcripts start from one or two promoters.
     All papillomaviruses exhibit extreme specificity for infection on epithelial cells. Although the mechanism of infection is not fully understood, the papillomavirus epitheliotrophy resides for the most part in the interaction of specific transcription factors with the viral regulatory region known as the long control region (LCR). Infection with papillomaviruses normally results in hyperproliferation of the host cell and in certain types it may lead to transformation and immortalization. This is because papillomaviruses express two or more protein products that transiently disrupt the cell cycle and stimulate cell division, knocking out at the same time the cellular mechanisms for growth inhibition. For a productive infection, papillomaviruses require terminally differentiated cells. This papillomavirus biology feature has impeded the full reproduction of their life cycle because the lack of highly efficient models of epithelial terminal differentiation in vitro. Nevertheless, most of the different stages in the papillomaviruses life cycle have been established using genetic engineering and molecular biology strategies.

HPV Life Cycle

    Because of the importance of HPV to public health and the intensive research this virus has received, the HPV-16 life cycle will be used as an example. The papillomavirus life cycle starts with the infection of the host cell. This process is largely unknown, but it is accepted that there is not a specific target receptor on the cell membrane. When the virus DNA is released within the nucleus, numerous cellular transcription factors interact with the non-coding viral regulatory region (LCR) starting transcription of the two HPV-16 transforming early genes (E6 and E7). After translation, the transforming proteins interact with the cellular antioncogenic regulators p53 and RB thus disrupting the cell cycle and inhibiting growth arrest. Concomitantly the viral genes E1 and E2 are expressed, regulating viral DNA replication and transcription. In genital HPV E2 represses early transcription by interacting with specific target sites within the LCR and displacing the basal transcription machinery. In animal papillomavirus and cutaneous HPVs E2 activate several promoters including the late promoters. It is not clear whether E2 stimulates genital HPVs late transcription. Following physical interaction between E2 and E1 proteins, papillomavirus genome replicates at low level (~20 copies/cell) in a “theta” replication mode. In differentiated cells, HPVs  replicate in high copy number (>100 copies per cell) in a rolling circle replication mode. At this stage, late transcription starts with the production of the capsid proteins which have the capacity to self-assemble into virions. It is not known how the papillomavirus DNA is packaged into de virion nor the mechanism of virus release.

Virion Structure

    Papillomavirus particles are constituted by the products of the L1 (Major capsid protein) and L2 (Minor capsid protein) genes. L1 is the most conserved region mong papillomaviruses. Virions are approximately 55nm in diameter and are composed of 72 capsomers, arranged on the surface of a T=7 icosahedron. The capsomers located at each of the 12 vertices, are pentavalent (i.e. each is surrounded by five adjacent capsomers), and the other 60 capsomers are hexavalent (each adjacent to six capsomers). HPV virions are produced in the upper strata of infected epithelium.

Back to LTG Home Page