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    Friday, 19 April 2013 10:28

    The Human Papillomavirus

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    The 3D model of HPVPapillomaviruses are a very diverse group of viruses that infect human skin and mucosal cells, which serve as a barrier between the environment and a human being. Most representatives of this group do not cause any symptoms, but highly pathogenic types may cause cancer. Ancient literature contains the first known mention of skin warts. The first classification of warts was introduced by Roman physician Aulus Cornelius Celsus in 25 AD, and the assumption that warts may be transmitted via infection originated even earlier. However, the viral nature of papillomas was not demonstrated until the beginning of the twentieth century (reviewed in 4). The first papillomavirus was isolated in 1933 by the American virologist Richard Shope, who also isolated an influenza virus.

    The evolutionary history of papillomaviruses seems to coincide with the origin of higher-order vertebrates, amniotes (including reptiles, birds, and mammals). Mammalian skin structure appears to make them the most suitable hosts for the papillomaviruses, and — today — papillomaviruses are widespread in mammals and rarely found in birds. The relationship between papillomaviruses and similar groups of DNA-viruses, such as polyomaviruses, is not well-demonstrated at the present time. There are more than a hundred types of papillomaviruseshigh-risk that can infect humans. These are collectively referred to as human papilloma viruses or HPV and are divided into (HR) and low-risk (LR) types by their carcinogenic properties. HPV are transmitted through direct skin-to-skin contact, and approximately 30 types are transmitted sexually. LR HPV are much more common than HR HPV among humans and often do not cause any symptoms. In fact, only 18 types of HPV pose a cancer risk, mostly for anogenital cancers.

    Current research suggests that LR HPVs produce more virions and infect more human hosts whereas HR types are less virulent but more difficult for the immune system to neutralize. The most dangerous HR HPV types are also the most widespread, HPV16 (reference strain) and HPV18, and the main cause of skin warts (especially in the anogenital zone) are HPV types 6 and 11. These and several other types of HPV attract serious attention.

    Human papilloma virus particles lack a lipid envelope and are relatively small, with a diameter of only about 30 nm. In comparison, the human immunodeficiency virus (HIV) and influenza virus virions are enveloped by a lipid bilayer derived from the host cell and are approximately four times larger. The papillomavirus genome consists of double-stranded DNA decorated and packed by histones of the host cell. It encodes two types of proteins, early (E) proteins and late (L) proteins: early HPV proteins maintain regulatory functions (and are responsible for oncotransformation of the host cell in the case of HR types), and late proteins form the capsid of the virion. The life cycle of HPV is bound to the life cycle of its host cells, keratinocytes, and HPV can only be cultivated in special organotypic raft cultures containing a population of cells at different developmental stages — similar to the skin of a living organism. Keratinocytes are the main cells of epidermis, the outermost layer of the skin. Actively dividing young keratinocytes are found near the basal membrane that separates the epidermis from other layers of the skin and move towards the skin surface during maturation. Viral particles infect non-differentiated cells, and new virions are produced inside the keratinocytes during the terminal stage of differentiation.

    The HPV early proteins are responsible for maintaining a proper amount of viral DNA inside the host cell nucleus. However, they also coordinate the expression of viral genes. Proteins E1 and E2 form a complex with viral DNA, which recruits the cell replication systems. Proteins E6 and E7 are responsible for the carcinogenic effect in HR HPV types. E6 is able to bind to the tumor suppressor p53 and promote its ubiquitination and degradation. Protein E7 binds several cell proteins and tumor suppressors, including theretinoblastoma protein. The activity of the E6 and E7 proteins leads to uncontrolled cell division.

    Late proteins of HPV form the viral capsid and mediate packaging of DNA into the virion. The pentamer-forming L1 protein is the major component of the HPV capsid, and the L2 protein is a minor constituent. The HPV capsid looks roughly spherical, but, in fact, it has a icosahedral symmetry with the triangulation number that equals 7. Rather than a structure based on pentamers mixed with hexamers (like that of the soccer ball), the HPV capsid is composed of 72 L1 pentamers of two different types — 60 hexavalent pentamers and 12 pentavalent pentamers (reviewed in 2, chapter 3). Remarkably, the fold of HPV L1 proteins is similar to that of human nucleoplasmins, the proteins that regulate the assembly of nucleosomes. Whether they share a common ancestor or whether their similarity is the result of convergent evolution is not yet clear. Perhaps the interaction between L1 and nucleosomes on viral DNA is crucial for the encapsidation of the HPV genetic material.

    One monomer of L2 is associated with each L1 pentamer of the HPV virion, and current research suggests that L2 is crucial for DNA recruitment to the viral particle. Some hypothesize that L2 — as well as L1 — may interact not with viral DNA but rather with its histones. To date, however, much of the process through which HPV DNA is packed inside the virion remains unknown. One facet of the process that is known may make HPV an important tool in human gene therapy: any segment of DNA less than 8 kb long may be packed inside the capsid [link], which enables the development and use of HPV-based transformation vectors. Interestingly, human cyclophilin participates in HPV capsid unpacking, a mechanism that has also been demonstrated for HIV.

    A growing interest in HPV research can be partially — if not wholly — attributed to discovery of the relationship between HPV and cancer and the subsequent Nobel Prize in Physiology or Medicine (2008) awarded for this work. German scientist Harald zur Hausen has shown that nearly all cases of cervical cancer are the result of HPV infection. Vaccines against HPV are currently being actively developed and introduced, and the main targets for such vaccines include the most dangerous and common HPV types: HPV6, HPV11, HPV16, HPV18.

    Dr. Christopher Buck from the U.S. National Cancer Institute: Current vaccines against human papillomaviruses (HPVs) are a triumph of applied structural virology. However, the current vaccines, which use recombinant virus-like particles composed of the L1 major capsid protein, do not protect against all disease-causing HPV types. Fortunately, a new generation of HPV vaccines targeting conserved „Achilles’ heel“ epitopes present in the L2 minor capsid protein promise to offer broad protection against all HPVs, including all types that cause cancer, as well as types that cause benign skin warts (for which the papillomavirus family is named). Current knowledge about the structure, dynamics, and function of L2 during the infectious entry process is very limited. This structural information is desperately needed to inform the development of pan-protective HPV vaccines.

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