Papillomaviridae is a family of non-enveloped double-stranded DNA viruses whose members are known as papillomaviruses. Several hundred species of papillomaviruses, traditionally referred to as "types", have been identified infecting all carefully inspected mammals, but also other vertebrates such as birds, snakes, turtles and fish. Infection by most papillomavirus types, depending on the type, is either asymptomatic (e.g. most Beta-PVs) or causes small benign tumors, known as papillomas or warts (e.g. human papillomavirus 1, HPV6 or HPV11). Papillomas caused by some types, however, such as human papillomaviruses 16 and 18, carry a risk of becoming cancerous.
Papillomaviruses are usually considered as highly host- and tissue-tropic, and are thought to rarely be transmitted between species. Papillomaviruses replicate exclusively in the basal layer of the body surface tissues. 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 (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. Additionally, there are descriptions of the presence of papillomavirus DNA in the blood and in the peripheral blood mononuclear cells.
Papillomaviruses were first identified in the early 20th century, when it was shown that skin warts, or papillomas, could be transmitted between individuals by a filterable infectious agent. In 1935 Francis Peyton Rous, who had previously demonstrated the existence of a cancer-causing sarcoma virus 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
There are over 100 species of papillomavirus recognised, though the ICTV officially recognizes a smaller number, categorized into 53 genera, as of 2019. All papillomaviruses (PVs) have similar genomic organizations, and any pair of PVs contains at least five homologous genes, although the nucleotide sequence may diverge by more than 50%. Phylogenetic algorithms 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, but adaptive radiations, occasional zoonotic events and recombinations may also impact their diversification. Their basic genomic organization appears maintained for a period exceeding 100 million years, and these sequence comparisons have laid the foundation for a PV taxonomy, which is now officially recognized by the International Committee on Taxonomy of Viruses. 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, which are identified by Greek letters. Minor branches are considered species 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 below the level of "species". Additionally, phylogenetic groupings at higher taxonomic level have been proposed.
This classification may need revision in the light of the existence of papilloma–polyoma virus recombinants. Additional species have also been described. Sparus aurata papillomavirus 1 has been isolated from fish.
The family contains two subfamilies and 53 genera, listed hereafter (-virinae denotes subfamilies and -virus denotes genera):
Subfamily: Firstpapillomavirinae
Alphapapillomavirus Betapapillomavirus Chipapillomavirus Deltapapillomavirus Dyochipapillomavirus Dyodeltapapillomavirus Dyoepsilonpapillomavirus Dyoetapapillomavirus Dyoiotapapillomavirus Dyokappapapillomavirus Dyolambdapapillomavirus Dyomupapillomavirus Dyonupapillomavirus Dyoomegapapillomavirus Dyoomikronpapillomavirus Dyophipapillomavirus Dyopipapillomavirus Dyopsipapillomavirus Dyorhopapillomavirus Dyosigmapapillomavirus Dyotaupapillomavirus Dyothetapapillomavirus Dyoupsilonpapillomavirus Dyoxipapillomavirus Dyozetapapillomavirus Epsilonpapillomavirus Etapapillomavirus Gammapapillomavirus Iotapapillomavirus Kappapapillomavirus Lambdapapillomavirus Mupapillomavirus Nupapillomavirus Omegapapillomavirus Omikronpapillomavirus Phipapillomavirus Pipapillomavirus Psipapillomavirus Rhopapillomavirus Sigmapapillomavirus Taupapillomavirus Thetapapillomavirus Treisdeltapapillomavirus Treisepsilonpapillomavirus Treisetapapillomavirus Treisiotapapillomavirus Treiskappapapillomavirus Treisthetapapillomavirus Treiszetapapillomavirus Upsilonpapillomavirus Xipapillomavirus Zetapapillomavirus
Subfamily: Secondpapillomavirinae Alefpapillomavirus
Human papillomaviruses
In 2014, 174 human papillomavirus types had been completely sequenced according to the International Human Papillomavirus Reference Center. They have been divided into five genera: Alphapapillomavirus, Betapapillomavirus, Gammapapillomavirus, Mupapillomavirus and Nupapillomavirus. At least 200 additional viruses have been identified that await sequencing and classification.
Animal papillomaviruses
Around 280 papillomaviruses have been identified in other animals, with mammalian, avian, reptilian, and fish hosts.
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 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. 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 (CRPV) can cause protuberant warts in its native host, the North American rabbit genus Sylvilagus. These horn-like warts may be the original basis for the urban legends of the American antlered rabbit the Jackalope and European Wolpertinger. 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 (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, the African multimammate rat and the Eurasian harvest mouse. However, there are no papillomaviruses known to be capable of infecting laboratory mice. A mouse papillovirus (MmuPV1) capable of infecting laboratory mice was developed in 2011 for research purposes.
Twenty types have been identified in seals.
Four papillomaviruses are known to infect birds: Fringilla coelebs papillomavirus 1, Francolinus leucoscepus papillomavirus 1, Psittacus erithacus papillomavirus 1 and Pygoscelis adeliae papillomavirus 1. All these species have a gene (E9) of unknown function, suggesting a common origin.
Evolution The evolution of papillomaviruses is thought to be slow compared to many other virus types, but there are no experimental measurements currently available.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, although there are strong evidences against the hypothesis of coevolution. 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. Cutaneotropic HPV types are occasionally exchanged between family members during the entire lifetime, but other donors should also be considered in viral transmission.
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 bonobos (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.
The most recent common ancestor of this group of viruses has been estimated to have existed .Willemsen A, Bravo IG (2019) Origin and evolution of papillomavirus (onco)genes and genomes. Philos Trans R Soc Lond B Biol Sci. 374(1773):20180303
There are five main genera infecting humans (Alpha, Beta, Gamma, Mu and Nu). The most recent common ancestor of these genera evolved -.Murahwa AT, Nindo F, Onywera H, Meiring TL, Martin DP, Williamson AL (2019) Evolutionary dynamics of ten novel Gamma-PVs: insights from phylogenetic incongruence, recombination and phylodynamic analyses. BMC Genomics 20(1):368 The most recent ancestor of the gamma genus was estimated to have evolved between and .
Structure
Papillomaviruses are non-enveloped, meaning that the outer shell or capsid of the virus is not covered by a lipid membrane. 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. Self-assembled virus-like particles composed of L1 are the basis of a successful group of prophylactic HPV vaccines designed to elicit virus-neutralizing antibodies that protect against initial HPV infection. As such, papillomaviridæ are stable in the environment.
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 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 vaccines.
The viral capsid consists of 72 capsomeres of which 12 are five-coordinated and 60 are six-coordinated capsomeres, arranged on a T = 7d icosahedral surface lattice.
Tissue specificity