The Importance of HPV Genotyping

Human Papillomavirus (HPV) is not a single entity; it is a diverse family of over 200 distinct viruses. These specific viral strains are referred to as genotypes. In clinical practice, HPV genotyping is critical because the specific type of virus an individual is infected with largely dictates their risk of developing cervical dysplasia, cancer, or other benign conditions like genital warts.

High-Risk vs. Low-Risk Genotypes

Genotypes are broadly categorized based on their oncogenic potential:

• Low-Risk Types (e.g., 6 and 11): These types rarely cause cancer. They are primarily responsible for benign epithelial proliferations, such as anogenital warts and recurrent respiratory papillomatosis.
• High-Risk Types (e.g., 16, 18, 31, 33, 45, 52, 58): These oncogenic types are capable of integrating into host DNA and causing cellular transformations. Types 16 and 18 are exceptionally aggressive and are collectively responsible for roughly 70% of all cervical cancers globally.

What the Test Detects

Clinical HPV tests use molecular biology techniques (like PCR) to detect the DNA or messenger RNA (mRNA) of high-risk HPV types in a sample of cervical cells. Many modern tests provide specific genotyping for types 16 and 18, while reporting the other high-risk types as a pooled positive result. Testing for low-risk types is generally not recommended clinically, as the presence of these viruses does not alter the management of cancer prevention.

Guiding Clinical Decisions

Genotyping heavily influences clinical management algorithms. For example, a patient with a mildly abnormal Pap smear (ASC-US) who tests positive for a generic high-risk HPV pool may be referred for a colposcopy. However, a patient who specifically tests positive for HPV 16 or 18 may be fast-tracked for immediate colposcopy regardless of their cytology results, due to the aggressive nature of these specific viral strains.

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. 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 Subfamily: Secondpapillomavirinae Alefpapillomavirus 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. 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.

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