Papillomaviruses

Topic-8-
 Papillomaviruses
Diseases:

• Human papillomavirus (HPV) causes papillomas, which are benign

tumors of squamous cells, eg warts on the skin.

• Some HPV, eg, HPV-16, are implicated as the cause of carcinomas,

especially carcinoma of the cervix.
 Papillomaviruses
Important Properties:
• Nonenveloped viruses with ds circular DNA and an icosahedral nucleocapsid.

• Members of the papovavirus family (pa: papillomaviruses, po: polyomaviruses, va: vacuolating agents). The
papillomaviruses are slightly larger than polyomaviruses

• Two of the early genes are implicated in carcinogenesis. They encode early proteins (E6
and E7) that inactivate proteins encoded by tumor suppressor genes in human cells,
eg, the p53 and the retinoblastoma (RB) gene, respectively. This inactivation leads to
the transformation of a normal cell into a cancer cell.

• At least 100 types classified on the basis of DNA restriction fragment analysis.

• Predilection of certain types to infect certain tissues i.e. tissue specific ex. skin warts are caused by HPV-1
through HPV-4. Genital warts are caused by HPV-6 and HPV-11. Approximately 30 types of HPV infect the
genital tract.
Papillomavirus genome and encoded late proteins. Labelled late proteins are L1, L2
(capsid proteins), early proteins are E6, E7 (oncogenic proteins), E4, E5, and E1, E2
(DNA replication proteins). LCR is the long control region

E6: targets degradation of p53

E7: binds to the retinoblastoma
protein
E2: transcriptional regulatory
protein with an auxillary role in
viral DNA replication
 Summary of Replicative Cycle
• The virus grows poorly in cell culture  little is known about its replication.

• In human tissue, infectious virus particles are found in the terminally differentiated
squamous cells rather than in the basal cells (dividing epidermal cells).

• In malignant cells, viral DNA is integrated into host cell DNA in the vicinity of cellular
proto-oncogenes, and E6 and E7 are overexpressed.

• In latently infected, nonmalignant cells, the viral DNA is episomal and E6 and E7 are not
overexpressed.

• This difference occurs because another early gene coding for E2 protein, controls E6 and
E7 protein expression. The E2 protein gene is functional when the viral DNA is episomal
but is inactivated when it is integrated.
 Transmission and epidemiology
• Transmission primarily by skin-to-skin contact and by genital
contact.

• Genital warts are among the most common sexually transmitted

diseases.

• Skin warts are more common in children and young adults and
tend to regress in older adults.

• Species specific
 Pathogenesis and immunity
• Papillomaviruses multiply only in proliferating stratified squamous epithelium which cannot be grown as
conventional cell cultures. The point of attack is often where one type of cell changes to another (e.g., the
junction of the columnar epithelium of the cervical canal with the stratified squamous epithelium of the outer
cervix).

• A characteristic feature of the benign skin warts is hyperkeratosis (i.e. a massive proliferation of the keratinized
layers of the dermis).

• Infection of squamous epithelial cells and induction of cytoplasmic vacuole within those cells. These vacuolated
cells, called koilocytes, are the hallmark of infection by these viruses.

• Most warts are benign and do not progress to malignancy.

• HPV infection is associated with carcinoma of the uterine cervix and penis.

• The histology of condylomata acuminata is quite similar to skin warts except that hyperkeratosis is not a
significant feature. The presence of vacuolated cells known as koilocytes (empty cells) is diagnostic but the
apparently empty vacuoles contain an enormous number of virions.

• The proteins encoded by viral genes, E6 and E7, interfere with the growth-inhibitory activity of the proteins
Papillomavirus pathogenesis
 Koilocyte in cervical scraping. The double
nucleus, which is characteristic, is
surrounded by an area of unstained
Penile warts (condylomata acuminata) cytoplasm
LSIL: Low-grade squamous
intraepithelial lesions

HSIL: High-grade
squamous intraepithelial
lesions

CIN: Cervical
intraepithelial neoplasia

Dysplasia: Abnormal
development of organs or
cells
 Clinical Findings
• Papillomas of various organs are caused by specific HPV.

• Skin warts (occur in large numbers anywhere on the skin esp. on the hands, knees, and
feet) and plantar warts (on the soles of the feet) are caused primarily by HPV-1 through
HPV-4.

• Genital warts (condylomata acuminata) are caused primarily by HPV-6 and HPV-11; in
men, they occur on the penis around the glans and prepuce or within the urethral meatus
and urethra itself or around the anus and within the rectum. In women, they occur on
the vulva, in the vagina, on the cervix and around the anus.

• Carcinoma of the uterine cervix, the penis, and the anus as well as premalignant lesions
called intraepithelial neoplasia, are associated with infection by HPV-16 and HPV-18.

• Occult premalignant lesions of the cervix and penis can be revealed by applying acetic
acid to the tissue. (Acetowhitening due to an increase in light scattering of nucleus and cytoplasm upon addition of
acetic acid)
 Laboratory Diagnosis
• Infections are usually diagnosed clinically.

• The presence of koilocytes in the lesions indicates HPV infection.

• DNA hybridization tests to detect the presence of viral DNA are

commercially available.

• Diagnostic tests based on detection of Abs in a patient’s serum or

on isolation of the virus from a patient’s tissue are not used.
 Treatment and Prevention

• The usual treatment for genital warts is podophyllin; alpha interferon is also effective and is better
at preventing recurrences than are non-antiviral treatments.

• Liquid nitrogen is commonly used for skin warts.

• Plantar warts can be removed surgically or treated with salicylic acid topically.

• Cidofovir may be useful in the treatment of severe HPV infections.

• There is no vaccine against HPV. An experimental vaccine consisting of the L1 capsid protein of
HPV did reduce the incidence of both HPV-16 infections and HPV-16-induced cervical
intraepithelial neoplasia.

• The role of cesarean section in preventing transmission of HPV from a mother with genital warts to
her newborn is uncertain.
 Control

• Warts, especially on the feet, are readily acquired in swimming pools and changing
rooms, where adequate hygienic measures should be maintained.

• Measures for preventing genital warts are similar to those for other sexually
transmitted diseases.
 Glossary
• Episome: Any accessory extrachromosomal replicating genetic element that can exist
either autonomously or integrated with chromosome

• Hyperkeratosis: Excess keratin formation on skin surface

• Condylomata acuminate: A small benign wart on or around the genitals and anus

• Urethral meatus: External orifice or opening of the urethra

• Neoplasia: The pathological process that results in the formation and growth of a tumor

• Occult: Hidden and difficult to be seen