The Papovaviridae family is made up of papovaviruses, which are viruses with small, enveloped, icosahedral capsids and double-stranded, circular DNA. The term papova comes from the first two letters of the virus names (pa, papillomaviruses; po, polyomaviruses; and va, vacuolating agents). Papillomavirus and Polyomavirus are the two genera within the family. The genus Papillomavirus is currently divided into a new family Papovaviridae, and the genus Polyomavirus is divided into a new family Polyomaviridae.
The proteins encoded by papovaviruses promote cell growth. They cause lytic infections as well as tumors (benign or malignant). Depending on the host cells infected, these viruses can cause lytic, chronic, latent, or transforming infections.
Human papillomaviruses (HPVs) are the causative agents of papillomas, which are the benign tumors of squamous cells or warts on the skin. These are also associated with cancerous conditions in humans, such as cervical carcinoma. HPVs causing diseases in humans are summarized in the table below.
|Papillomavirus||Skin wartsBenign head and neck tumorsAnogenital wartsCancerous conditions (oral premalignant lesions and oral squamous cell carcinoma, intraepithelial cervical neoplasia and cancer)Recurrent respiratory papillomatosis|
|BK virus||Renal diseases (hemorrhagic cystitis and urethral stenosis)|
|JC virus||Progressive multifocal leukoencephalopathy|
HPVs have been classified into 16 groups (A–P) with at least 70 types based on DNA homology, tissue tropism, and association with oncogenesis.
Properties of the Virus
Human papillomaviruses exhibit the following characteristics:
- They are double-stranded DNA viruses that do not have an envelope.
- The viruses are slightly larger than polyomaviruses, with a diameter of 50–55 nm.
- They have an icosahedral capsid with 72 capsomeres.
- The viral genome is made up of approximately 3000 base pairs of supercoiled, double-stranded DNA (bp). The DNA contains seven to eight early genes (E1–E8) and two late genomes (L1 and L2). All of these genes are found on a single strand, the “” strand. Two of the early genes, E6 and E7, have been linked to cancer, whereas E1 and E2 are involved in DNA replication.
Papillomaviruses have a preference for skin epithelial cells and mucous membranes. Virus replication in epithelial cells is dependent on specific factors that are present in sequentially differentiated epithelial cells.
The virus’s early genes are in charge of cell growth and replication of the viral genome during cell division. The virus-induced cell growth thickens the stratum spinosum’s basal and prickle cell layers. Late genes encode for the expression of structural proteins found in the differentiated upper layers of the skin. As a result, the tissues are excreted along with the dead cells of the upper layer.
Antigenic and genomic properties
The HPVs are extremely diverse. More than 100 distinct HPVs have been identified based on the homology of their genomes. Certain HPV types have a distinct proclivity for infecting specific tissues. Around 30 different types of HPVs infect the genital tract, with HPV-6 and HPV-11 causing genital warts. HPV types 1–6 are the most common cause of skin warts.
Virus Isolation and Animal Susceptibility
Human papillomaviruses cannot grow in cell culture. As a result, cell cultures are ineffective for diagnosing HPV infections.
Pathogenesis and Immunity
Human papillomaviruses exhibit a high level of host specificity. They have a strong preference for the skin as well as the mucous membrane. HPV infection is spread through close contact and is initiated by infections of the skin or mucous membranes. The tissue tropism and disease manifestation are determined by the HPV type that causes the disease.
Pathogenesis of human papilloma virus infections
Following infection, the virus replicates in the skin’s squamous epithelium, causing warts, and in the mucous membrane, causing epithelial proliferation, resulting in oral, genital, and conjunctival papillomas. Warts form as a result of virus-induced cell growth and thickening of the stratum spinosum’s basal and prickle layers, as well as the stratum granulosum.
The presence of koilocytes is a defining feature of HPV infections of the skin. These koilocytes are enlarged keratocytes with well-defined halos encircling small nuclei. HPV infection always results in a localized infection, and warts usually resolve on their own, possibly as a result of an immune response.
Human papillomavirus has also been linked to the development of oral premalignant and malignant conditions in humans. HPV-16, as well as HPV-18, HPV-33, and HPV-35, have been linked to
- Verruciform proliferation in the oral cavity
- Premalignant lesions in the oral cavity
- Oral squamous cell carcinoma.
The precise mechanism responsible for papilloma resolution is unknown. Cell-mediated immunity, on the other hand, appears to play an important role in disease resolution. Conditions that suppress cell-mediated immunity, such as those found in HIV patients and those receiving immunosuppressive therapy, cause an exacerbation of HPV infection and a more severe manifestation of the disease.
Human papilloma virus infection causes:
- cutaneous warts
- benign head and neck tumors
- genital warts
- cancerous conditions in humans
HPV-2, HPV-4, and HPV-7 are the most common causes of cutaneous warts. Warts typically appear on the hands and feet after a 3–4 month incubation period, depending on the HPV type and site of infection. They can be flat, plantar, or dome in shape.
Children and young adults are the most likely to develop plantar and flat warts. Warts are typically benign and self-limiting conditions that resolve over time.
|Common wart||1, 2, 4, 7, 26, 29|
|Flat wart||3, 10, 27, 28, 41|
|Epidermodysplasia verruciformis||5, 8, 9, 14, 15, 17, 19, 20, 21–25, 36, 38, 46|
|Warts in organ transplant patients||75, 77|
|Hand warts of meat and animal handlers||7|
Benign tumors of head and neck
Oral papilloma, laryngeal papilloma, and conjunctival papilloma are examples of these.
Oral papillomas are typically single, but they can be multiple. Sessile, verrucous, and white with raised borders, they are sessile, verrucous, and white. These lesions are most commonly found on the lips, hard palate, or gingiva. HPV-13 and HPV-32 are the most common causes of focal epithelial hyperplasia, also known as Heck disease. This condition is characterized by multiple, smooth, sessile nodules on the mucosal surface of the lower lip or on the buccal mucosa. This condition has been described in North Americans.
HPV-6 and HPV-11 cause laryngeal papillomas, which can be fatal in children. This is the most common benign laryngeal epithelial tumor.
|Laryngeal papilloma||6, 11|
|Oral papilloma||2, 6, 11, 16|
HPV-6 and HPV-11 are responsible for genital warts, also known as condyloma acuminata. The condition typically manifests as solitary or multiple cerebriform and pink lesions on the nonkeratinized mucosa rather than the keratinized mucosa. During sexual activity involving orogenital contact, these genital lesions may spread to the oral cavity.
Clinical syndromes associated with HPV: Anogenital wart
|Condyloma acuminatum||1, 2, 6, 10, 11, 16, 30, 44, 45|
|Cervical intraepithelial neoplasia, cancer||11, 16, 18, 31, 33, 35, 42–44|
Certain types of HPV—most commonly, HPV-16, but also, less frequently, HPV-18, HPV-33, and HPV-35—have been linked to oral premalignancy and malignancy in humans. These diseases are characterized by verruciform proliferations in the oral cavity. HPV-16 and HPV-18-caused oral premalignant lesions and oral squamous cell carcinoma are the most commonly associated with intraepithelial cervical neoplasia and cancer. Over the course of 1–4 years, the condition progresses from mild to moderate neoplasia to severe dysplasia or carcinoma in situ.
HPV infections are found all over the world.
Reservoir, source, and transmission of infection
Human papillomaviruses have been found in the oral cavity of 6–10% of children and adolescents, and in 5–80% of healthy adults. HPVs can be found in genital secretions and skin sheddings that contain the virus. The primary source of infection is infected humans. Asymptomatic virus shedding in body secretions facilitates infection transmission to other human hosts.
The infections are spread primarily through skin-to-skin contact and genital contact. They are transmitted as follows:
- most frequently through sexual contact (HPV-16, HPV-18)
- by direct contact through abrasions in the skin and mucosa; and
- As in the case of laryngeal papilloma, by passing through an infected birth canal (types 6 and 11).
Histopathological examination is used to diagnose warts. The presence of prickle cell hyperplasia and excessive keratin production (hyperkeratosis) is indicative of the condition. Human papillomavirus infection can be identified by the presence of clumps of round coalesced cytotic squamous epithelial cells in Papanicolaou smears. Because HPVs do not grow in cell lines, cell cultures are ineffective. Serology is rarely employed. Typing virus isolates can be accomplished through immunohistochemical detection of HPV structural proteins.
Warts regress over time. Months to years Warts can be removed using surgical cryotherapy, electrocautery, or chemical reagents.
Prevention and Control
There are no specific HPV prevention measures available. Direct contact with infected warts should be avoided to reduce the risk of transmission. Safe sexual practices will be beneficial in preventing HPV transmission through sexual contact.
Simian virus 40 (SV40) is the prototype polyomavirus that has been extensively studied for eliciting various virus properties. Human polyomaviruses, such as the BK and JC viruses, typically cause asymptomatic infection. Polyomaviruses (poly, many; oma, tumor) are 45 nm in diameter and are smaller than papillomaviruses. They are nonenveloped viruses with icosahedral capsids of 72 capsids.
The viral genome is a double-stranded DNA with less nucleic acid, about 5000 bp. The genomes of polyomaviruses (BK, JC, and SV40) are very similar. The genome is divided into three sections: early, late, and noncoding.
The early region encodes a nonstructural transformation protein, whereas the late region encodes three viral capsid proteins, VP1, VP2, and VP3. The noncoding region contains the site of DNA replication origin. The table below summarizes the differences between HPV and polyomaviruses.
|Virion size (diameter)||55 nm||45 nm|
|Genome size||8103 bp||5103 bp|
|Coding information||On one strand||On both strands|
|Result of natural infection||Benign tumor||Inapparent|
|Target tissue||Surface epithelia||Internal organs|
|Transform cells in vitro||Rarely||Yes|
|Genome in transformed cells||Episomal in warts; integrated in carcinoma||Integrated|
|Viruses infecting humans||Human papillomavirus||BK and JC viruses; SV40|
|Clinical syndromes||Skin warts, genital warts laryngeal papillomas, cervical carcinoma||Progressive multifocal leukoencephalopathy and nephropathy in transplant recipients|
Different polyomaviruses have different host preferences. Human polyomaviruses, such as JC and BK, are thought to enter the body through the respiratory tract and then infect lymphocytes and the kidneys. The BK viruses cause latent kidney and B cell infection. The pathogenesis of human polyomavirus infection in humans is determined by the host’s immune status. Virus replication is inhibited in the immunocompetent host. Immune suppression in patients undergoing organ transplantation or suffering from AIDS results in the reactivation of latent JC and BK viruses. Virus reactivation causes virus shedding and symptomatic infection in these patients. When BK viruses reactivate, they cause severe urinary tract infection and virus excretion in the urine. Reactivation of JC viruses causes viremia and virus spread to the central nervous system (CNS), resulting in CNS infection.
In immunocompetent hosts, primary infection with human polyomaviruses is mostly asymptomatic. The tissues are reactivated in immunocompromised hosts, causing a variety of serious diseases.
Both the JC and BK viruses are common. By the age of 15, the majority of people have been infected by these two viruses. Both viruses are most likely transmitted through the respiratory system.
- The BK virus is linked to hemorrhagic cystitis in bone marrow recipients. It also causes urethral stenosis in kidney transplant recipients.
- The JC virus was first isolated from the brain of a Hodgkin’s disease patient who developed progressive multifocal leukoencephalopathy (PML). PML is a fatal subacute demyelinating disease of the central nervous system. This disease typically affects immunocompromised patients, such as those suffering from AIDS, Hodgkin’s disease, or chronic lymphocytic leukemia.
- Although SV40 has oncogenic potential in newborn hamsters, it is not linked to any human disease. The SV40, on the other hand, is important for public health. Previously, some batches of polio vaccines prepared in simian cell culture were contaminated with undetected SV40 virus.
- Although SV40 has oncogenic potential in newborn hamsters, it is not linked to any human disease. The SV40, on the other hand, is important for public health. Previously, some batches of polio vaccines made in simian cell culture were contaminated with undetected SV40 virus in primary monkey cell cultures. However, no SV40-related tumors have been reported so far, despite the fact that many people were vaccinated with contaminated polio vaccines.
Electron microscopy is useful for detecting JC virus in PML brain tissue and kidney transplant recipient urine. Immunoperoxidase and in situ immunofluorescence are rapid detection methods for viral antigen in brain tissue obtained through biopsy or autopsy.
BK polyomavirus is isolated from urine using human diploid fibroblast culture, while JC virus is isolated from urine and brain tissue using human fetal glial cell culture. To distinguish these two viruses, a hemagglutination inhibition test is performed.
There is no specific antiviral treatment for polyomavirus infections in humans. Polyomavirus infection is difficult to prevent due to the viruses’ pervasiveness.
Source : Textbook of Microbiology and Immunology, 2/eParija p.485-682