PAPILLOMAVIRUSES AND POLYOMAVIRUSES

Maria Cielo B. Malijan, MD, DPPS, FPSDBP

PAPOVAVIRIDAE
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PAPOVAVIRIDAE

POLYOMA AND PAPILLOMAVIRUSES

SIMILARITIES:
Morphology Nucleic composition Transforming capabilities

PAPILLOMAVIRIDAE

POLYOMAVIRIDAE

DIFFERENCES
biology genome organization

PAPILLOMAVIRIDAE

PAPILLOMAVIRIDAE
Virion: Composition: Genome: Proteins: Envelope:

Icosahedral, 55nm in diameter DNA (10%), Protein (90%) dsDNA, circular, 8kbp
2 structural proteins, cellular histones condense DNA in virion

none

Outstanding characteristics:
Stimulate cell DNA synthesis Restricted host range and tissue tropism Significant cause of human cancer, especially cervical cancer Viral oncoproteins interact with cellular tumor suppressor proteins

Papilloma virus

All 72 capsomeres are pentamers of the major structural protein.

PAPILLOMAVIRUSES
Highly tropic for epithelial cells of the skin and mucous membranes Viral nucleic acid can be found in the basal stem cells

Late gene expression (capsid proteins) is restricted to the uppermost layer of differentiated keratinocytes
Stages in viral replicative cycles dependent on specific factors that are present in the sequential differentiated states of the epithelial cells (difficult to cultivate in vitro)

BIOLOGIC CHARACTERISITICS
Species specific Failure of terminal differentiation Replication terminally differentiated layer of the squamous epithelium Viral DNA and RNA transcripts for early gene expression basal layer

SKIN WART (PAPILLOMA)

Stratum corneum Stratum granulosum Capsid protein Virus particles Replicating virus particles Expression of early genes Viral DNA (low copy number)

Stratum spinosum

Basal cell (mitosis)

PATHOGENESIS AND PATHOLOGY

Transmission: close contact From the surface of the papillomatous lesion

Formation of warts at the cutaneous and mucosal sites

Skin warts, plantar warts, flat warts, anogenital warts, laryngeal papillomas, cancer of the cervix, vulva, penis and anus and a subset of head and neck cancers

Examples of Association of Human Papillomaviruses with Clinical Lesions

Human Papillomavirus Type
1 2, 4, 27, 57 3, 10, 28, 49, 60, 76, 78 5, 8, 9, 12, 17, 20, 36, 47 Plantar warts Common skin warts Cutaneous lesions Epidermoplasia verruciformis

Clinical Lesion

Suspected Oncogenic Potential

Benign Benign Low Mostly benign, but some progress to malignancies

6, 11, 40, 42-44, 54, Anogenital condylomas; laryngeal papillomas; Low 61, 70, 72, 81 dysplasias and intraepithelial neoplasias (mucosal sites) 7 16, 18, 30, 31, 33, 35, 39, 45, 51-53, 56, 58, 59, 66, 68, 73, 82 Hand warts of butchers High-grade dysplasias and carcinomas of genital mucosa; laryngeal and esophageal carcinomas Low High correlation with genital and oral cancer especially cervical cancer

Examples of Association of Human Papillomaviruses with Clinical Lesions

Human Papillomavirus type
1 2, 4, 27, 57 3, 10, 28, 49, 60, 76, 78 5, 8, 9, 12, 17, 20, 36, 47 Plantar warts Common skin warts Cutaneous lesions Epidermoplasia verruciformis

Clinical Lesion

Suspected Oncogenic Potential

Benign Benign Low Mostly benign, but some progress to malignancies

6, 11, 40, 42-44, 54, Anogenital condylomas; laryngeal papillomas; Low 61, 70, 72, 81 dysplasias and intraepithelial neoplasias (mucosal sites) 7 16, 18, 30, 31, 33, 35, 39, 45, 51-53, 56, 58, 59, 66, 68, 73, 82 Hand warts of butchers High-grade dysplasias and carcinomas of genital mucosa; laryngeal and esophageal carcinomas Low High correlation with genital and oral cancer especially cervical cancer

High cancer risk!

CONDITIONS CAUSED
Warts (common, plantar or flat) Epidermodysplasia verruciformis Condyloma acuminata (Genital warts) Laryngeal papillomas Human Papillomas in cancer
Squamous cell carcinoma Premalignant and malignant lesions of the uterine cervix, vagina and vulva

Epidemiology and Clinical Associations

Warts (common, plantar or flat)
Children and young adults Contact and minor abrasions No specific predisposing factors Extensive disease primary immunodeficiencies; on immunosuppressive therapy

Epidemiology and Clinical Associations

Warts (common, plantar or flat)
HPV types 1 through 3 5 to 15 years old

HPV-4
HPV-7

20 to 25 years old
meat handlers

MODE OF TRANSMISSION : direct contact or wound abrasion No specific predisposition. But for excessive warty disease, may be associated with primary immunodeficiencies.

Spontaneous regression

Epidemiology and Clinical Associations

Epidermodysplasia verruciformis
Warts and macular lesions Familial; autosomal recessive Depressed cell-mediated immunity Lifetime persistence of disseminated wart lesions HPV serotypes 5, 8, 9, 12, 14, 15, 17, and 19 to 25 Natural route of transmission not known

Epidemiology and Clinical Associations

Epidermodysplasia verruciformis
Malignant transformation
25% HPV-5 Sun-exposed areas

Epidemiology and Clinical Associations

Condyloma acuminata (Genital warts)
Young adults
HPV types 6 or 11 Venereal transmission Predisposing factors
Sexual promiscuity Hormonal imbalance (e.g., in pregnancy)

Regress Recurrence extensive lesions Malignant transformation vulva, penis and anus

Epidemiology and Clinical Associations

Condyloma acuminata (Genital warts)
Older adults
75% - unprotected intercourse

Children
Sexual abuse Perinatal transmission

Epidemiology and Clinical Associations

Condyloma acuminata (genital warts)
High incidence of HPV DNA in persons with no clinically diagnosable HPV-associated disease Subclinical
Cofactors trauma of sexual activity and smoking

Epidemiology and Clinical Associations

Recurrent Respiratory Papillomas (Laryngeal Papillomas)
Juvenile type
Children younger than 5 years of age HPV types 6 or 11 Perinatal transmission

Adults
Frequent and rapid recurrence Malignant conversion
rare radiation or heavy smoking

Epidemiology and Clinical Associations

Epidermal Infections are associated with:
Antibodies
Serotype-specific IgM and IgG

Cell-mediated immunity
Correlated with resolution of warts

PATHOGENESIS AND PATHOLOGY

Behavior of HPV lesions is influenced by immunologic factors CMI Nearly all HPV infections are cleared and become undetectable in 2 to 3 years

Cervical cancer persistent with high risk HPV is a necessary component to progression to malignancy

CLINICAL FINDINGS AND EPIDEMIOLOGY

An estimated 660 million have HPV infection, the most common viral infection of the reproductive tract.

An estimated 6.2 million new cases reported annually in the U.S. Peak incidence occurs in adolescents and young adults

 HPV accepted as the cause of anogenital cancers. 99% of cervical cancer patients and over 80% of anal cancers are linked to genital infections with papillomaviruses HPV 16 and 18 found most frequently in cervical cancers, responsible for 70% of all cervical cancers (HPV 16 being the most common)

 Anal cancer - associated with high-risk HPV infection At risk:

Immunocompromised individuals Men who have sex with men Oropharyngeal cancers (subtype of head and neck squamous cell carcinomas) Linked to HPV 16

 Anogenital warts
HPV 6 and 11

Laryngeal papillomas in children (recurrent respiratory papillomatosis)

HPV 6 and 11 Passage through the birth canal Causes obstruction (asphyxiation)

Benign Genital Condylomas

HPV 6 and 11

 Normal Skin high prevalence of HPV DNA in healthy adults Immunosuppressed individuals have an increased incidence of warts and cancer of the cervix

All HPV cancers occur more frequently in persons with HIV/ AIDS

Human Papillomaviruses in Cancer

Squamous cell carcinoma
HPV-6
Juvenile laryngeal papillomatosis Condyloma acuminata

HPV-5; less commonly HPV-8 and HPV-14

Epidermodysplasia verruciformis

Cervical Neoplasia
Premalignant and malignant lesions of the uterine cervix, vagina and vulva
HPV-16
most common 25% - CIN III 33% to 70% - invasive cervical CA

Others HPV-18, 33 and 35 Smoking

Treatment
Removal of the lesion
Podophyllin Cryosurgery common warts Laser therapy refractory genital or respiratory lesions

Treatment
Immunomodulation
Alpha-interferon
Systemic and intralesional Extensive refractory genital and respiratory papillomatosis

Specific
Topical idoxuridine
Extensive genital warts

Systemic cytotoxic chemotherapy

Treatment
Hypnosis and suggestion
Hand warts Highly effective

PREVENTION AND CONTROL

AGAINST CERVICAL CANCER
Quadrivalent vaccine (HPV 6, 11, 16 and 18) Bivalent vaccine (HPV 16 and 18)

Not effective against established HPV disease Target: adolescent and young adult females Immunity maybe up to 5 years Not recommended for pregnant women

POLYOMAVIRIDAE

POLYOMAVIRIDAE
Virion: Composition: Genome: Proteins: Envelope:

Icosahedral, 45nm in diameter DNA (10%), Protein (90%) dsDNA, circular, 8kbp
3 structural proteins, cellular histones condense DNA in virion

none

Outstanding characteristics:
Stimulate cell DNA synthesis Viral oncoproteins interact with cellular tumor suppressor proteins Important model tumor viruses Human viruses can cause human neurologic and renal disease May cause human cancer

DNA-containing tumor viruses

SV40 from monkeys and humans BK virus JC virus KI virus Merkel cell virus from humans Murine polyoma virus

POLYOMAVIRUS REPLICATION
GENOME contains Early regions Late regions

POLYOMAVIRUS REPLICATION
EARLY REGIONS Expressed soon after infection of cells LATE REGIONS Codes for the synthesis of coat proteins

Transforming proteins must be continually synthesized for cells to stay transformed

No role in transformation Not expressed in transformed cells

BK AND JC VIRUSES
Widely distributed in human populations Antibodies present in 70-80% of adult sera

Infection occurs in childhood

Persists in kidneys and lymphoid tissues of healthy individuals after primary infection May reactivate when host immune response is impaired

BK AND JC VIRUSES
Viral reactivation and shedding of virus in urine are asymptomatic in immunocompetent persons Commonly isolated from immunocompromised patients

BK AND JC VIRUSES
BK VIRUS Causes: hemorrhagic cystitis in bone marrow transplant recipients Polyoma-virus associated virus nephropathy in renal transplant patients JC VIRUS Associated with human brain tumors but an etiologic role is not yet established Causes: progressive multifocal leukoencephalopathy
(fatal in patients with depressed CMI due to immunosuppressive therapies or infection with HIV)

Oncogenicity
No data exist linking JCV or BKV to human carcinomas

Progressive Multifocal Leukoencephalopathy (PML)

Oligodendrocytes JCV most common; others SV40-like virus

Gray and white matter

Diffuse throughout the neuroaxis Small, discrete areas of demyelination confluence

Progressive Multifocal Leukoencephalopathy (PML)

Diagnosis
Brain biopsy Serology
Not helpful High prevalence of antibody in the general population Impaired immune responses

Progressive Multifocal Leukoencephalopathy (PML)

Treatment
None

Prophylaxis
Alpha-interferon in renal transplant patients

KI AND WU VIRUS, MERKEL CELL POLYOMAVIRUS

KI AND WU VIRUSES Discovered in 2007 in nasopharyngeal aspirates from children with respiratory infections MERKEL CELL POLYOMAVIRUS 2008 Identified in Merkel cell carcinomas (rare skin tumors of neuroendocrine origin)

SV40
Replicates in certain types of monkey and human cells Highly tumorigenic in experimental inoculated animals May be transmitted via fecal-oral route in humans

Transmission electron micrograph of Polyoma virus SV40