Papillomavirus
Encyclopedia
Papillomaviridae is an ancient taxonomic family
Family (biology)
In biological classification, family is* a taxonomic rank. Other well-known ranks are life, domain, kingdom, phylum, class, order, genus, and species, with family fitting between order and genus. As for the other well-known ranks, there is the option of an immediately lower rank, indicated by the...

 of non-enveloped
Viral envelope
Many viruses have viral envelopes covering their protein capsids. The envelopes typically are derived from portions of the host cell membranes , but include some viral glycoproteins. Functionally, viral envelopes are used to help viruses enter host cells...

 DNA virus
DNA virus
A DNA virus is a virus that has DNA as its genetic material and replicates using a DNA-dependent DNA polymerase. The nucleic acid is usually double-stranded DNA but may also be single-stranded DNA . DNA viruses belong to either Group I or Group II of the Baltimore classification system for viruses...

es, collectively known as papillomaviruses. Several hundred species of papillomaviruses, traditionally referred to as "types", have been identified infecting all carefully inspected birds and mammals, but also a small number of reptiles, in particular turtles and tortoises. Infection by most papillomavirus types, depending on the type, is either asymptomatic (e.g. Type 6, Type 11) or causes small benign tumors, known as papilloma
Papilloma
Papilloma refers to a benign epithelial tumor growing exophytically in finger-like fronds. In this context papilla refers to the projection created by the tumor, not a tumor on an already existing papilla . When used without context, it frequently refers to infections caused by human...

s or wart
Wart
A wart is generally a small, rough growth, typically on a human’s hands or feet but often other locations, that can resemble a cauliflower or a solid blister. They are caused by a viral infection, specifically by human papillomavirus 2 and 7. There are as many as 10 varieties of warts, the most...

s. Papillomas caused by some types, however, such as human papillomavirus
Human papillomavirus
Human papillomavirus is a member of the papillomavirus family of viruses that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the skin or mucous membranes...

es 16 and 18, carry a risk of becoming cancerous
Malignant transformation
Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor....

.

Papillomaviridæ are highly host-
Host tropism
Host tropism is the name given a process of tropism that determines which cells can become infected by a given pathogen. Various factors determine the ability of a pathogen to infect a particular cell. Viruses, for example, must bind to specific cell surface receptors to enter a cell...

 and tissue-tropic
Tropism
A tropism is a biological phenomenon, indicating growth or turning movement of a biological organism, usually a plant, in response to an environmental stimulus. In tropisms, this response is dependent on the direction of the stimulus...

, and are rarely transmitted between species. Papillomaviruses replicate exclusively in the basal layer
Stratum germinativum
The stratum basale is the deepest layer of the five layers of the epidermis, which is the outer covering of skin in mammals. The stratum basale is a continuous layer of cells...

 of the body surface tissues
Stratified squamous epithelium
A stratified squamous epithelium consists of squamous epithelial cells arranged in layers upon a basement membrane. Only one layer is in contact with the basement membrane; the other layers adhere to one another to maintain structural integrity...

. All known papillomavirus types infect a particular body surface, typically the skin or mucosal epithelium of the genitals, anus, mouth, or airways. For example, human papillomavirus
Human papillomavirus
Human papillomavirus is a member of the papillomavirus family of viruses that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the skin or mucous membranes...

 (HPV) type 1 tends to infect the soles of the feet, and HPV type 2 the palms of the hands, where they may cause warts
Plantar wart
-External links:* at the Mayo Clinic website* at The Merck Manual* at dermnet.com...

.

Papillomaviruses were first identified in the early 20th century, when it was shown that skin wart
Wart
A wart is generally a small, rough growth, typically on a human’s hands or feet but often other locations, that can resemble a cauliflower or a solid blister. They are caused by a viral infection, specifically by human papillomavirus 2 and 7. There are as many as 10 varieties of warts, the most...

s, or papilloma
Papilloma
Papilloma refers to a benign epithelial tumor growing exophytically in finger-like fronds. In this context papilla refers to the projection created by the tumor, not a tumor on an already existing papilla . When used without context, it frequently refers to infections caused by human...

s, could be transmitted between individuals by a filterable infectious agent. In 1935 Francis Peyton Rous
Francis Peyton Rous
Peyton Rous born in Baltimore, Maryland in 1879 and received his B.A. and M.D. from Johns Hopkins University. He was involved in the discovery of the role of viruses in the transmission of certain types of cancer...

, who had previously demonstrated the existence of a cancer-causing sarcoma virus
Rous sarcoma virus
Rous sarcoma virus is a retrovirus and is the first oncovirus to have been described: it causes sarcoma in chickens.As with all retroviruses, it reverse transcribes its RNA genome into cDNA before integration into the host DNA.-History:...

 in chickens, went on to show that a papillomavirus could cause skin cancer in infected rabbits. This was the first demonstration that a virus could cause cancer in mammals.

Taxonomy of papillomaviruses

Papillomaviruses (PVs) have similar genomic organizations, and any pair of PVs contains at least five homologous gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

s, although the nucleotide sequence may diverge by more than 50%. Phylogenetic algorithm
Algorithm
In mathematics and computer science, an algorithm is an effective method expressed as a finite list of well-defined instructions for calculating a function. Algorithms are used for calculation, data processing, and automated reasoning...

s that permit the comparison of homologies led to phylogenetic trees that have a similar topology, independent of the gene analyzed. Phylogenetic studies strongly suggest that PVs normally evolve together with their mammalian and bird host species, do not change host species, do not recombine, and have maintained their basic genomic organization for a period exceeding 100 million years. These sequence comparisons have laid the foundation for a PV taxonomy, which is now officially recognized by the International Committee on Taxonomy of Viruses
International Committee on Taxonomy of Viruses
The International Committee on Taxonomy of Viruses is a committee which authorizes and organizes the taxonomic classification of viruses. They have developed a universal taxonomic scheme for viruses and aim to describe all the viruses of living organisms. Members of the committee are considered to...

. All PVs form the family Papillomaviridae, which is distinct from the Polyomaviridae thus eliminating the term Papovaviridae. Major branches of the phylogenetic tree of PVs are considered genera
Genus
In biology, a genus is a low-level taxonomic rank used in the biological classification of living and fossil organisms, which is an example of definition by genus and differentia...

, which are identified by Greek letters. Minor branches are considered species
Species
In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring. While in many cases this definition is adequate, more precise or differing measures are...

 and unite PV types that are genomically distinct without exhibiting known biological differences. This new taxonomic system does not affect the traditional identification and characterization of PV "types" and their independent isolates with minor genomic differences, referred to as "subtypes" and "variants", all of which are taxa
Taxon
|thumb|270px|[[African elephants]] form a widely-accepted taxon, the [[genus]] LoxodontaA taxon is a group of organisms, which a taxonomist adjudges to be a unit. Usually a taxon is given a name and a rank, although neither is a requirement...

 below the level of "species".

Animal papillomaviruses

Individual papillomavirus types tend to be highly adapted to replication in a single animal species. In one study, researchers swabbed the forehead skin of a variety of zoo animals and used PCR
Polymerase chain reaction
The polymerase chain reaction is a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence....

 to amplify any papillomavirus DNA that might be present. Although a wide variety of papillomavirus sequences were identified in the study, the authors found little evidence for inter-species transmission. Interestingly, one zookeeper was found to be transiently positive for a chimpanzee-specific papillomavirus sequence. However, the authors note that the chimpanzee-specific papillomavirus sequence could have been the result of surface contamination of the zookeeper's skin, as opposed to productive infection.

Cottontail rabbit papillomavirus
Shope papilloma virus
The cottontail rabbit papilloma virus , or Shope papilloma virus, is a type I virus under the Baltimore scheme, possessing a nonsegmented dsDNA genome. It infects rabbits, causing keratinous carcinomas, typically on or near the animal’s head...

 (CRPV) can cause protuberant warts (see images) in its native host, the North American rabbit genus Sylvilagus. These horn-like warts may be the original basis for the urban legend
Urban legend
An urban legend, urban myth, urban tale, or contemporary legend, is a form of modern folklore consisting of stories that may or may not have been believed by their tellers to be true...

s of the American antlered rabbit the Jackalope
Jackalope
The jackalope is a mythical animal of North American folklore described as a jackrabbit with antelope horns or deer antlers and sometimes a pheasant's tail . The word "jackalope" is a portmanteau of "jackrabbit" and "antalope", an archaic spelling of "antelope". It is also known as Lepus...

 and European Wolpertinger
Wolpertinger
In Bavarian folklore, a wolpertinger is an animal said to inhabit the alpine forests of Bavaria in Germany. It has a body comprised from various animal parts — generally wings, antlers, tails and fangs, all attached to the body of a small mammal...

. European domestic rabbits (genus Oryctolagus) can be transiently infected with CRPV in a laboratory setting. However, since European domestic rabbits do not produce infectious progeny virus, they are considered an incidental or "dead-end" host for CRPV.

Inter-species transmission has also been documented for bovine papillomavirus
Bovine papillomavirus
Bovine papillomavirus is a group of DNA viruses of the family Papillomaviridae that are common in cattle. Infection causes warts of the skin and alimentary tract, and more rarely cancers of the alimentary tract and urinary bladder...

 (BPV) type 1. In its natural host (cattle), BPV-1 induces large fibrous skin warts. BPV-1 infection of horses, which are an incidental host for the virus, can lead to the development of benign tumors known as sarcoids. The agricultural significance of BPV-1 spurred a successful effort to develop a vaccine against the virus.

A few reports have identified papillomaviruses in smaller rodents, such as Syrian hamsters
Golden Hamster
The golden hamster or Syrian hamster, Mesocricetus auratus, is a very well known member of the rodent subfamily Cricetinae, the hamsters. In the wild they are now considered vulnerable. Their numbers have been declining due to loss of habitat and deliberate destruction by humans. However, they are...

, the African multimammate rat
Mastomys
Mastomys is a genus of rodent in the family Muridae.It contains the following species:* Awash Mastomys * Southern Multimammate Mouse * Guinea Multimammate Mouse...

 and the Eurasian harvest mouse. However, there are no papillomaviruses known to be capable of infecting laboratory mice
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...

. The lack of a tractable mouse model for papillomavirus infection has been a major limitation for laboratory investigation of papillomaviruses.

Evolution

The evolution of papillomaviruses is slow compared to many other virus types. This is probably because the papillomavirus genome is composed of genetically stable double-stranded DNA that is replicated with high fidelity by the host cell's DNA replication machinery.

It is believed that papillomaviruses generally co-evolve with a particular species of host animal over many years. In a particularly speedy example, HPV-16 has evolved slightly as human populations have expanded across the globe and now varies in different geographic regions in a way that probably reflects the history of human migration.

Other HPV types, such as HPV-13, vary relatively little in different human populations. In fact, the sequence of HPV-13 closely resembles a papillomavirus of bonobo
Bonobo
The bonobo , Pan paniscus, previously called the pygmy chimpanzee and less often, the dwarf or gracile chimpanzee, is a great ape and one of the two species making up the genus Pan. The other species in genus Pan is Pan troglodytes, or the common chimpanzee...

s (also known as pygmy chimpanzees). It is not clear whether this similarity is due to recent transmission between species or because HPV-13 has simply changed very little in the six or so million years since humans and bonobos diverged.

Structure

Papillomaviruses are non-enveloped, meaning that the outer shell or capsid
Capsid
A capsid is the protein shell of a virus. It consists of several oligomeric structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The capsid encloses the genetic...

 of the virus is not covered by a lipid membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...

. A single viral protein, known as L1, is necessary and sufficient for formation of a 55-60 nanometer capsid composed of 72 star-shaped capsomers (see figure). Like most non-enveloped viruses, the capsid is geometrically regular and presents icosahedral symmetry
Icosahedral symmetry
A regular icosahedron has 60 rotational symmetries, and a symmetry order of 120 including transformations that combine a reflection and a rotation...

. Self-assembled virus-like particles composed of L1 are the basis of a successful group of prophylactic HPV vaccine
HPV vaccine
The human papilloma virus vaccine prevents infection with certain species of human papillomavirus associated with the development of cervical cancer, genital warts, and some less common cancers...

s designed to elicit virus-neutralizing antibodies that protect against initial HPV infection. As such, papillomaviridæ are stable in the environment
Environment (biophysical)
The biophysical environment is the combined modeling of the physical environment and the biological life forms within the environment, and includes all variables, parameters as well as conditions and modes inside the Earth's biosphere. The biophysical environment can be divided into two categories:...

.

The papillomavirus genome is a double-stranded circular DNA molecule ~8,000 base pairs in length. It is packaged within the L1 shell along with cellular histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...

 proteins, which serve to wrap and condense DNA.

The papillomavirus capsid also contains a viral protein known as L2, which is less abundant. Although not clear how L2 is arranged within the virion, it is known to perform several important functions, including facilitating the packaging of the viral genome into nascent virions as well as the infectious entry of the virus into new host cells. L2 is of interest as a possible target for more broadly protective HPV vaccine
HPV vaccine
The human papilloma virus vaccine prevents infection with certain species of human papillomavirus associated with the development of cervical cancer, genital warts, and some less common cancers...

s.

Tissue specificity

Papillomaviruses replicate exclusively in keratinocyte
Keratinocyte
Keratinocytes are the predominant cell type in the epidermis, the outermost layer of the human skin, constituting 95% of the cells found there. Those keratinocytes found in the basal layer of the skin are sometimes referred to as "basal cells" or "basal keratinocytes"...

s. Keratinocytes form the outermost layers of the skin, as well as some mucosal surfaces
Mucous membrane
The mucous membranes are linings of mostly endodermal origin, covered in epithelium, which are involved in absorption and secretion. They line cavities that are exposed to the external environment and internal organs...

, such as the inside of the cheek or the walls of the vagina. These surface tissues, which are known as stratified squamous epithelia
Squamous epithelium
In anatomy, squamous epithelium is an epithelium characterised by its most superficial layer consisting of flat, scale-like cells called squamous epithelial cells...

, are composed of stacked layers of flattened cells. The cell layers are formed through a process known as cellular differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...

, in which keratinocytes gradually become specialized, eventually forming a hard, crosslinked surface that prevents moisture loss and acts as a barrier against pathogens. Less-differentiated keratinocyte stem cells, replenished on the surface layer, are thought to be the initial target of productive papillomavirus infections. Subsequent steps in the viral life cycle are strictly dependent on the process of keratinocyte differentiation. As a result, papillomaviruses can only replicate in body surface tissues.

Infectious entry

Papillomaviruses gain access to keratinocyte stem cells through small wounds, known as microtraumas, in the skin or mucosal surface. Interactions between L1 and sulfated sugars on the cell surface promote initial attachment of the virus. The virus is then able to get inside from the cell surface via interaction with a specific receptor, likely via the alpha-6 beta-4 integrin, and transported to membrane-enclosed vesicles
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...

 called endosome
Endosome
In biology, an endosome is a membrane-bound compartment inside eukaryotic cells. It is a compartment of the endocytic membrane transport pathway from the plasma membrane to the lysosome. Molecules internalized from the plasma membrane can follow this pathway all the way to lysosomes for...

s. The capsid protein L2 disrupts the membrane of the endosome, allowing the viral genome to escape and traffic, along with L2, to the cell nucleus.

Viral Persistence

After successful infection of a keratinocyte, the virus expresses E1 and E2 proteins, which are for replicating and maintaining the viral DNA as a circular episome. The viral oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...

s E6 and E7 promote cell growth by inactivating the tumor suppressor proteins p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...

 and pRb
Retinoblastoma protein
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in the majority types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide...

. Keratinocyte stem cells in the epithelial basement layer can maintain papillomavirus genomes for decades.

Production of progeny virus

The expression of the viral late genes, L1 and L2, is exclusively restricted to differentiating keratinocytes in the outermost layers of the skin or mucosal surface. The increased expression of L1 and L2 is typically correlated with a dramatic increase in the number of copies of the viral genome. Since the outer layers of stratified squamous epithelia are subject to relatively limited surveillance by cells of the immune system, it is thought that this restriction of viral late gene expression represents a form of immune evasion.

New infectious progeny virus are assembled in the cell nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...

. Papillomaviruses have evolved a mechanism for releasing virions into the environment. Other kinds of non-enveloped animal viruses utilize an active lytic process to kill the host cell, allowing release of progeny virus particles. Often this lytic process is associated with inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

, which might trigger immune attack against the virus. Papillomaviruses exploit desquamation
Desquamation
Desquamation , also called skin peeling, is the shedding of the outermost membrane or layer of a tissue, such as the skin.-Skin:Normal, nonpathologic desquamation of the skin occurs when keratinocytes, after moving apically over about 14 days, are individually shed unnoticeably...

 as a stealthy, non-inflammatory release mechanism.

Cancer

Although some papillomavirus types can cause cancer in the epithelial tissues they inhabit, cancer is not a typical outcome of infection. The development of papillomavirus-induced cancers typically occurs over the course of many years.

Laboratory study

The fact that the papillomavirus life cycle strictly requires keratinocyte differentiation has posed a substantial barrier to the study of papillomaviruses in the laboratory, since it has precluded the use of conventional cell lines
Cell culture
Cell culture is the complex process by which cells are grown under controlled conditions. In practice, the term "cell culture" has come to refer to the culturing of cells derived from singlecellular eukaryotes, especially animal cells. However, there are also cultures of plants, fungi and microbes,...

 to grow the viruses. Because infectious BPV-1 virions can be extracted from the large warts the virus induces on cattle, it has been a workhorse model papillomavirus type for many years. CRPV, rabbit oral papillomavirus (ROPV) and canine oral papillomavirus (COPV) have also been used extensively for laboratory studies.

Some sexually transmitted HPV types have been propagated using a mouse “xenograft” system, in which HPV-infected human cells are implanted into immunodeficient mice. More recently, some groups have succeeded in isolating infectious HPV-16 from human cervical lesions. However, isolation of infectious virions using this technique is arduous and the yield of infectious virus is very low.

The differentiation of keratinocytes can be mimicked in vitro by exposing cultured keratinocytes to an air/liquid interface. The adaptation of such “raft culture” systems to the study of papillomaviruses was a significant breakthrough for in vitro study of the viral life cycle. However, raft culture systems are relatively cumbersome and the yield of infectious HPVs can be low.

The development of a yeast-based system that allows stable episomal HPV replication provides a convenient, rapid and inexpensive means to study several aspects of the HPV lifecycle (Angeletti 2002). For example, E2-dependent transcription, genome amplification and efficient encapsidation of full-length HPV DNAs can be easily recreated in yeast (Angeletti 2005).

Recently, transient high-yield methods for producing HPV pseudoviruses
Vector (molecular biology)
In molecular biology, a vector is a DNA molecule used as a vehicle to transfer foreign genetic material into another cell. The four major types of vectors are plasmids, viruses, cosmids, and artificial chromosomes...

 carrying reporter genes has been developed. Although pseudoviruses are not suitable for studying certain aspects of the viral life cycle, initial studies suggest that their structure and initial infectious entry into cells is probably similar in many ways to authentic papillomaviruses.

Genetic organization

The papillomavirus genome is divided into an early region (E), encoding various genes that are expressed immediately after initial infection of a host cell, and a late region (L) encoding the capsid genes L1 and L2. All the genes are encoded on one DNA strand (see figure). This represents a dramatic difference between papillomaviruses and polyomavirus
Polyomavirus
Polyomavirus is the sole genus of viruses within the family Polyomaviridæ. Murine polyomavirus was the first polyomavirus discovered by Ludwik Gross in 1953. Subsequently, many polyomaviruses have been found to infect birds and mammals...

es, since the latter virus type expresses its early and late genes by bi-directional transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...

 of both DNA strands. This difference was a major factor in establishment of the consensus that papillomaviruses and polyomaviruses probably never shared a common ancestor, despite the striking similarities in the structures of their virions.

Technical discussion of papillomavirus gene functions

Genes within the papillomavirus genome are usually identified after similarity with other previously identified genes. However, some spurious open reading frame
Open reading frame
In molecular genetics, an open reading frame is a DNA sequence that does not contain a stop codon in a given reading frame.Normally, inserts which interrupt the reading frame of a subsequent region after the start codon cause frameshift mutation of the sequence and dislocate the sequences for stop...

s might have been mistaken as gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

s simply after their position in the genome, and might not be true genes. This applies specially to certain E3, E4, E5 and E8 open reading frame
Open reading frame
In molecular genetics, an open reading frame is a DNA sequence that does not contain a stop codon in a given reading frame.Normally, inserts which interrupt the reading frame of a subsequent region after the start codon cause frameshift mutation of the sequence and dislocate the sequences for stop...

s.

E1

Encodes a protein that binds to the viral origin of replication
Origin of replication
The origin of replication is a particular sequence in a genome at which replication is initiated. This can either be DNA replication in living organisms such as prokaryotes and eukaryotes, or RNA replication in RNA viruses, such as double-stranded RNA viruses...

 in the long control region of the viral genome. E1 uses ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

 to exert a helicase
Helicase
Helicases are a class of enzymes vital to all living organisms. They are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separating two annealed nucleic acid strands using energy derived from ATP hydrolysis.-Function:Many cellular processes Helicases are a...

 activity that forces apart the DNA strands, thus preparing the viral genome for replication by cellular DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...

 factors.

E2

The E2 protein serves as a master transcriptional
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...

 regulator for viral promoters located primarily in the long control region. The protein has a transactivation
Transactivation
In molecular biology and genetics, transactivation is an increased rate of gene expression triggered either by biological processes or by artificial means.- Natural transactivation :...

 domain linked by a relatively unstructured hinge region to a well-characterized DNA binding domain. E2 facilitates the binding of E1 to the viral origin of replication. E2 also utilizes a cellular protein known as Bromodomain
Bromodomain
A bromodomain is a protein domain that recognizes acetylated lysine residues such as those on the N-terminal tails of histones. This recognition is often a prerequisite for protein-histone association and chromatin remodeling. The domain itself adopts an all-α protein fold, a bundle of four alpha...

-4 (Brd4) to tether the viral genome to cellular chromosomes. This tethering to the cell's nuclear matrix
Nuclear matrix
In biology, the nuclear matrix is the network of fibres found throughout the inside of a cell nucleus and is somewhat analogous to the cell cytoskeleton...

 ensures faithful distribution of viral genomes to each daughter cell after cell division. It is thought that E2 serves as a negative regulator of expression for the oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...

s E6 and E7 in latently HPV-infected basal layer keratinocytes. Genetic changes, such as integration of the viral DNA into a host cell chromosome, that inactivate E2 expression tend to increase the expression of the E6 and E7 oncogenes, resulting in cellular transformation and possibly further genetic destabilization.

E3

This small putative gene exists only in a few papillomavirus types. The gene is not known to be expressed as a protein and does not appear to serve any function.

E4

Although E4 proteins are expressed at low levels during the early phase of viral infection, expression of E4 increases dramatically during the late phase of infection. In other words, its “E” appellation may be something of a misnomer. In the case of HPV-1, E4 can account for up to 30% of the total protein at the surface of a wart. The E4 protein of many papillomavirus types is thought to facilitate virion release into the environment by disrupting intermediate filaments of the keratinocyte cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...

. Viral mutants incapable of expressing E4 do not support high-level replication of the viral DNA, but it is not yet clear how E4 facilitates DNA replication. E4 has also been shown to participate in arresting cells in the G2 phase of the cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...

.

E5

The E5 are small, very hydrophobic proteins that destabilise the function of many membrane proteins in the infected cell. The E5 protein of some animal papillomavirus types (mainly bovine papillomavirus
Bovine papillomavirus
Bovine papillomavirus is a group of DNA viruses of the family Papillomaviridae that are common in cattle. Infection causes warts of the skin and alimentary tract, and more rarely cancers of the alimentary tract and urinary bladder...

 type 1) functions as an oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...

 primarily by activating the cell growth-promoting signaling of platelet-derived growth factor
Platelet-derived growth factor
In molecular biology, platelet-derived growth factor is one of the numerous growth factors, or proteins that regulate cell growth and division. In particular, it plays a significant role in blood vessel formation , the growth of blood vessels from already-existing blood vessel tissue. Uncontrolled...

 receptors. The E5 proteins of human papillomaviruses associated to cancer, however, seem to activate the signal cascade initiated by epidermal growth factor
Epidermal growth factor
Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...

 upon ligand binding. HPV16 E5 and HPV2 E5 have also been shown to down-regulate the surface expression of major histocompatibility complex
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...

 class I proteins, which may prevent the infected cell from being eliminated by killer T cells.

E6

E6 is a 151 amino-acid peptide that incorporates a type 1 motif with a consensus sequence
Consensus sequence
In molecular biology and bioinformatics, consensus sequence refers to the most common nucleotide or amino acid at a particular position after multiple sequences are aligned. A consensus sequence is a way of representing the results of a multiple sequence alignment, where related sequences are...

 –(T/S)-(X)-(V/I)-COOH. It also has two zinc finger
Zinc finger
Zinc fingers are small protein structural motifs that can coordinate one or more zinc ions to help stabilize their folds. They can be classified into several different structural families and typically function as interaction modules that bind DNA, RNA, proteins, or small molecules...

 motifs.

E6 is of particular interest because it appears to have multiple roles in the cell and to interact with many other proteins. Its major role, however, is to mediate the degradation of p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...

, a major tumor suppressor
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...

 protein, reducing the cell's ability to respond to DNA damage.

E6 has also been shown to target other cellular proteins, thereby altering several metabolic pathway
Metabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...

s. One such target is NFX1-91
NFX1
Transcriptional repressor NF-X1 is a protein that in humans is encoded by the NFX1 gene.MHC class II gene expression is controlled primarily at the transcriptional level by transcription factors that bind to the X and Y boxes, two highly conserved elements in the proximal promoter of MHC class II...

, which normally represses production of telomerase
Telomerase
Telomerase is an enzyme that adds DNA sequence repeats to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from...

, a protein that allows cells to divide an unlimited number of times. When NFX1-91 is degraded by E6, telomerase levels increase, inactivating a major mechanism keeping cell growth in check. Additionally, E6 can act as a transcriptional cofactor—specifically, a transcription activator—when interacting with the cellular transcription factor, E2F1/DP1.

E6 can also bind to PDZ-domains
PDZ domain
The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals...

, short sequences which are often found in signaling proteins. E6's structural motif allows for interaction with PDZ domains on DLG (discs large) and hDLG (Drosophila large) tumor suppressor genes. Binding at these locations causes transformation of the DLG protein and disruption of its suppressor function. E6 proteins also interact with the MAGUK (membrane-associated guanylate kinase family) proteins. These proteins, including MAGI-1, MAGI-2, and MAGI-3 are usually structural proteins, and can help with signaling. More significantly, they are believed to be involved with DLG's suppression activity. When E6 complexes with the PDZ domains on the MAGI proteins, it distorts their shape and thereby impedes their function. Overall, the E6 protein serves to impede normal protein activity in such a way as to allow a cell to grow and multiply at the increased rate characteristic of cancer.

Since the expression of E6 is strictly required for maintenance of a malignant phenotype in HPV-induced cancers, it is an appealing target of therapeutic HPV vaccine
HPV vaccine
The human papilloma virus vaccine prevents infection with certain species of human papillomavirus associated with the development of cervical cancer, genital warts, and some less common cancers...

s designed to eradicate established cervical cancer tumors.

E7

In most papillomavirus types, the primary function of the E7 protein is to inactivate members of the pRb
Retinoblastoma protein
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in the majority types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide...

 family of tumor suppressor proteins. Together with E6, E7 serves to prevent cell death (apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

) and promote cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...

 progression, thus priming the cell for replication of the viral DNA. E7 also participates in immortalization of infected cells by activating cellular telomerase
Telomerase
Telomerase is an enzyme that adds DNA sequence repeats to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. This region of repeated nucleotide called telomeres contains non-coding DNA material and prevents constant loss of important DNA from...

. Like E6, E7 is the subject of intense research interest and is believed to exert a wide variety of other effects on infected cells. As with E6, the ongoing expression of E7 is required for survival of cancer cell lines, such as HeLa
HeLa
A HeLa cell is a cell type in an immortal cell line used in scientific research. It is the oldest and most commonly used human cell line. The line was derived from cervical cancer cells taken on February 8, 1951 from Henrietta Lacks, a patient who eventually died of her cancer on October 4, 1951...

, that are derived from HPV-induced tumors.

E8

Only a few papillomavirus types encode a short protein from the E8 gene. In the case of BPV-4
Bovine papillomavirus
Bovine papillomavirus is a group of DNA viruses of the family Papillomaviridae that are common in cattle. Infection causes warts of the skin and alimentary tract, and more rarely cancers of the alimentary tract and urinary bladder...

 (papillomavirus genus Xi), the E8 open reading frame may substitute for the E6 open reading frame, which is absent in this papillomavirus genus. These E8 genes are chemically and functionally similar to the E5 genes from some human papillomaviruses, and are also called E5/E8.

L1

L1 spontaneously self-assembles into pentameric capsomers. Purified capsomers can go on to form capsids, which are stabilized by disulfide bonds between neighboring L1 molecules. L1 capsids assembled in vitro are the basis of prophylactic vaccines against several HPV types. Compared to other papillomavirus genes, the amino acid sequences of most portions of L1 are well-conserved between types. However, the surface loops of L1 can differ substantially, even for different members of a particular papillomavirus species. This probably reflects a mechanism for evasion of neutralizing antibody responses elicited by previous papillomavirus infections.

L2

L2 exists in an oxidized state within the papillomavirus virion, with the two conserved cysteine residues forming an intramolecular disulfide
Disulfide
In chemistry, a disulfide usually refers to the structural unit composed of a linked pair of sulfur atoms. Disulfide usually refer to a chemical compound that contains a disulfide bond, such as diphenyl disulfide, C6H5S-SC6H5....

 bond. In addition to cooperating with L1 to package the viral DNA into the virion, L2 has been shown to interact with a number of cellular proteins during the infectious entry process. After the initial binding of the virion to the cell, L2 must be cleaved by the cellular protease furin
Furin
Furin is a protein that in humans is encoded by the FURIN gene. It was named furin because it was in the upstream region of an oncogene known as FES. The gene was known as FUR and therefore the protein was named furin...

. The virion is internalized, probably through a clathrin-mediated process, into an endosome, where acidic conditions are thought to lead to exposure of membrane-destabilizing portions of L2. The cellular proteins beta-actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...

 and syntaxin
Syntaxin
Syntaxins are a family of membrane integrated Q-SNARE proteins participating in exocytosis.- Domains :Syntaxins possess a single C-terminal transmembrane domain, a SNARE domain , and an N-terminal regulatory domain ....

-18 may also participate in L2-mediated entry events. After endosome escape, L2 and the viral genome are imported into the cell nucleus where they traffic to a sub-nuclear domain known as an ND-10 body that is rich in transcription factors. Small portions of L2 are well-conserved between different papillomavirus types, and experimental vaccines targeting these conserved domains may offer protection against a broad range of HPV types.

External links

  • Viralzone: Papillomaviridae
  • Los Alamos National Laboratory maintains a comprehensive (albeit somewhat dated) papillomavirus sequence database. This useful database provides detailed descriptions and references for various papillomavirus types.
  • A short video which shows the effects of papillomavirus on the skin of an Indonesian man with epidermodysplasia verruciformis
    Epidermodysplasia verruciformis
    Epidermodysplasia verruciformis is an extremely rare autosomal recessive genetic hereditary skin disorder associated with a high risk of carcinoma of the skin. It is characterized by abnormal susceptibility to human papillomaviruses of the skin...

    , the genetic inability to defend against some types of cutaneous HPV.
  • http://www.ncbi.nlm.nih.gov/ICTVdb/Ictv/fs_index.htm de Villiers, E.M., Bernard, H.U., Broker, T., Delius, H. and zur Hausen, H. Index of Viruses - Papillomaviridae (2006). In: ICTVdB - The Universal Virus Database, version 4. Büchen-Osmond, C (Ed), Columbia University, New York, USA.
  • 00.099. Papillomaviridae description In: ICTVdB - The Universal Virus Database, version 4. Büchen-Osmond, C. (Ed), Columbia University, New York, USA
The source of this article is wikipedia, the free encyclopedia.  The text of this article is licensed under the GFDL.
 
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