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Virus Description . Genus Papovaviridae Morphology Naked, icosahedral 55 nm 72 capsomeres 2 capsid proteins including 1 major (L1) and 1 minor (L2) Circular, ds DNA, 8 Kb Established as an episome, but it can integrate into the host DNA. Discovery.

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virus description
Virus Description
  • Genus

Papovaviridae

  • Morphology
    • Naked, icosahedral
    • 55 nm
    • 72 capsomeres
    • 2 capsid proteins including 1 major (L1) and 1 minor (L2)
    • Circular, ds DNA, 8 Kb

Established as an episome, but it can integrate into the host DNA

discovery
Discovery
  • Human papillomas (warts) were linked to a virus in 1907
  • Papillomavirus was first isolated in rabbits by Richard Shope; thus the first oncogenic strain was discovered
  • No further studies were conducted until the 1970’s
  • Once cervical cancer was linked to HPV, molecular virology allowed these studies to move forth
  • Papillomavirus is highly species specific
e1 e2 early viral protein expression non structural
E1 major protein

Involved in replication

Exhibits helicase activity

Forms complex, binds sequences at the origin of replication, and recruits polymerases and accessory proteins to mediate replication

E2 regulatory protein

For replication and transcription from E6 promoter, as well as DNA packaging

Helps to recruit E1, but also regulates viral transcription from early promoter

E1 & E2: Early Viral Protein Expression (Non-structural)
e4 e5
E4 & E5
  • The functions of E4 & E5 are not fully understood; however, they may be involved in late viral functions
e6 e7
E6 & E7
  • E6 & E7 interact with a many cellular proteins; therefore, influencing the outcome of an infection
  • E7 is responsible for the formation of papillomas
  • E6 & E7 act as viral oncoproteins of high risk HPVs, but they do not function as such in low risk HPVs
l1 l2 structural proteins
L1 (Major) and L2 (Minor) are structural proteins that are assembled late andspontaneously to form the icosahedral capsids

L1 (Major) makes up 80% of the viral capsid

L1& L2 Structural Proteins
hpv replication transcription in the epidermis
HPV Replication & Transcription in the Epidermis
  • Infects basal cells of dermal layer (low level of transcription & replication)
  • DNA amplification and capsid proteins made in the upper spinous layer
  • Transcription increases in the spinous layer
  • Squames released at surface to release viral particles
e6 e7 work together as viral oncoproteins to immortalize target cells
E6 binds to p53 tumor suppressor via p100 (cellular protein)

Targets p53 leading to degradation and down-regulation of pathways involved in cycle arrest and apoptosis

E7 binds to retinoblastoma (RB) tumor suppressor

Represses transcription of genes involved in apoptosis, as well as interferes with cell cycle regulation

E6 & E7 Work Together as Viral Oncoproteins to Immortalize target cells
clinical aspects of hpv
Clinical Aspects of HPV
  • There are approximately 138 HPV strains that have been sequenced
  • These include nongenital cutaneous, nongenital mucosal types, and anogenital types (developing around genital area or anal area)
  • Cancerous types exist in all of these categories
  • Low risk types HPV 6 & 11 are the most common low risk genital types
  • High risk types HPV 16 & 18 are the most common high risk genital types
slide14
Genital warts(sexually transmittled)

Condylomata acuminata - Cauliflowerlike

Genital warts -Smooth popular warts

Genital Flat warts -Flat warts

Bowenoid Papules -Small, elevated

Nongenital Warts

(non-sexually transmitted)Common warts

- Hands, fingers and knees

Plantar warts

-Feet

Flat warts

-Hands and face

Genital Warts vs. Nongenital Warts

slide15

Nongenital Mucosal Type

Nongenital Mucosal Disease

HPV Type

Respiratory papillomatosis

6, 11

Squamous cell carcinoma of the lung

6, 11, 16, 18

Laryngeal papilloma

6, 11, 30

Laryngeal carcinoma

16, 18

Maxillary sinus papilloma

57

Squamous cell carcinoma of the sinuses

16, 18

Conjunctival papillomas

6, 11

Conjunctival carcinoma

16

Oral focal epithelial hyperplasia (Heck disease)

13, 32

Oral carcinoma

16, 18

Oral leukoplakia

16, 18

Squamous cell carcinoma of the esophagus

16, 18

nongenital mucosal
Nongenital Mucosal

Laryngeal papilloma

Conjunctival papillomas

slide17

Nongenital Types

Nongenital Cutaneous Disease

HPV Type

Common warts (verrucae vulgaris)

1, 2, 4, 26, 27, 29, 41, 57, 65

Plantar warts (myrmecias)

1, 2, 4, 63

Flat warts (verrucae plana)

3, 10, 27, 28, 38, 41, 49

Butcher\'s warts (common warts of people who handle meat, poultry, and fish)

1, 2, 3, 4, 7, 10, 28

Mosaic warts

2, 27, 57

Ungual squamous cell carcinoma

16

Epidermodysplasia verruciformis (benign)

2, 3, 10, 12, 15, 19, 36, 46, 47, 50

Epidermodysplasia verruciformis (malignant or benign)

5, 8, 9, 10, 14, 17, 20, 21, 22, 23, 24, 25, 37, 38

Nonwarty skin lesions

37, 38

slide19

Intermediate intraepithelial neoplasia

31, 33, 35, 42, 44, 45, 51, 52

High-grade intraepithelial neoplasia

16, 18, 56, 58

Carcinoma of vulva

6, 11, 16, 18

Carcinoma of vagina

16

Carcinoma of cervix

16, 18, 31

Carcinoma of anus

16, 31, 32, 33

Carcinoma in situ of penis (erythroplasia of Queyrat)

16

Carcinoma of penis

16, 18

Anogenital Types

slide20

Anogenital Disease

HPV Type

Condylomata acuminata

6, 11, 30, 42, 43, 44, 45, 51, 52, 54

Bowenoid papulosis

16, 18, 34, 39, 42, 45

Bowen disease

16, 18, 31, 34

Giant condylomata (Buschke-Löwenstein tumors)

6, 11

Unspecified intraepithelial neoplasia

30, 34, 39, 40, 53, 57, 59, 61, 62, 64, 66, 67, 68, 69

Low-grade intraepithelial neoplasia

6, 11, 43

Anogenital Types

infection
Infection
  • Viral entry may result in a latent infection or can develop within 1-3 months, or may stay undetected for years
  • Lesion likely due to clonal expansion of infected cells
  • Infection can be subclinical or clinical
transmission
Transmission
  • HPV is released from the desquamating superficial keratinocytes of the infected stratified epithelia
  • Transmission of cutaneous HPVs occurs through direct contact with infected tissue or through indirect contact with contaminated objects and surfaces such as poolsides
  • Transmission of genital HPV typically occurs through sexual contact
hpv cervical disease
HPV & Cervical Disease
  • 99.7 % of cervical cancers

are a result of HPV-16 &

HPV-18

  • HPV infection of the cervix

corresponds to low-grade

CIN (Cervical intraepithelial

Neoplasia)

    • mostly flat aceto-whitening areas

including flat condyloma

progressive cervical disease
Progressive Cervical Disease
  • Starts as a benign noninvasive or squamous intraepithelial lesion (SIL) or CIN
  • Most low-grade intraepithelial lesions regress; however, some remain unchanged
  • 10-15% progress to moderate or severe dysplasia; carcinoma in situ
  • High grade CIN may develop into invasive cancer after years or decades
    • HPV 16, 18, and 45 are the most prevalent detected
detection via molecular assays
Detection Via Molecular Assays

Three molecular assays are used to detect HPV in exfoliated cell samples or tissues

  • Signal amplification assay
    • Hybrid Capture 2 assay (only FDA approved assay)
  • Target amplification assays
    • PCR & in situ PCR
  • Non-amplified hybridization assays
    • Dot blot hybridization (DB), Southern transfer hybridization (STH) and in situ hybridiation(ISH)
slide28

Normal Cells Progress to Dysplasia

http://www:pathology.washington.edu/clinical/HPV/

slide29

Moderate Dysplasia to Cancer

http://www:pathology.washington.edu/clinical/HPV/

host immune response
Host Immune Response
  • Most encounters of HPV are cleared by the host between 1-2 years
  • Strong immune response usually is not generated
  • HPV can be a chronic infection
  • Skin warts generate low levels of antibodies
  • 50% of IgG found in HPV 6 & 11 genital types
  • IgG and IgA humoral response to HPV 16 associated CIN found in 50-75%
  • Antibodies detected in 15-25% of those with no current infection (most likely indicates past infection)
host immune response1
Host Immune Response
  • Antibodies are rarely detected in patients with pre-malignant cervical lesions
  • Antibodies detected in 50% of women with late-stage invasive HPV-16 associated with cervical carcinoma
  • Cell mediated immunity (CMI) is probably extensively involved in control of the infection
    • High incidence of cutaneous and anogenital HPV associated disease is observed among patients with genetic or aquired CMI deficiencies
host immune response2
Host Immune Response
  • Immunological and genetic aspects likely to attribute to persistence and progression of CIN
    • Higher frequency found in HIV infected women
  • Functional alterations of LCs have been shown to correspond with initiation and progression of HPV related cervical disease
history of hpv detection
History of HPV Detection
  • 1927 Georges Papanicalaou did research on diagnostic cytology of the cervix
  • 1940s His research was published. First Paps were in Korea
  • 1950s Paps began being used widely
  • 1975 Harold zur Hausen linked HPV with cervical cancer
  • 1980s His team isolated several genotypes linked to cervical cancer and genital warts
  • 1999 PCR assay found HPV DNA in 99.7% of cervical cancers studied
genital hpv types
Genital HPV Types
  • Only 40 types of HPV infect the genital tract
  • Only these types can lead cause carcinoma:
    • Types 16, 31, 33, 35, 52, 58
    • Types 18, 39, 45, 70 (flat – in cervix, create tumors)
  • Infections with certain “high-risk” HPV types can progress to dysphasias or cancer of the cervix, penis, anus, vagina and tonsils.
  • Only 1% of HPV infections will progress to cervical cancer.
prevalence of hpv
Prevalence of HPV
  • HPV can show up in women on the cervix and the vulva, inside the surrounding areas of the vagina, and anus.
  • It is common for HPV to exhibit no symptoms
  • HPV can be acquired and cleared without the person ever knowing that they were infected
  • HPV is commonly passed unintentionally by people who have no symptoms
  • This is one reason why HPV is so common.
most women will be infected
Most Women will be Infected
  • HPV infection is estimated to involve 80% of the sexually active population.
  • As sexually active people you will probably contract HPV at some point in your life.
  • 3 of 4 Americans between the ages of 15 and 50 have been infected with HPV at some point.
  • Your immune system will most likely clear it.
  • HPV represents the most common sexually transmitted viruses.
uw students
A UW study found that more than 60% of college women became infected over 5 years.UW Students

SOURCE: GRAPH ADAPTED FROM R. L. WINER ET AL., AMERICAN JOURNAL OF EPIDEMIOLOGY157, 218 (2003)

hpv persistence
HPV Persistence
  • Most young women clear the virus, but it is unknown how many completely clear it.
  • Some HPV may go into remission after an active period of months or years, but they are not usually fully eliminated.
    • “Active viral infections typically re-emerge from latency during transient or permanent immunodeficiency associated with sunburn, pregnancy, physical and emotional stress, HIV infection and cancer chemotherapy.” (WSDOH)
  • There is no way to tell how long you have been infected or when HPV will express.
men and hpv
Men and HPV
  • Men also harbour and express HPV in the form of penile, perennial and urethral papillomas.
  • Men are much more likely to be carriers and not develop cancer.
  • A urethral swab for males to collect exfoliated cells for Pap analysis exists but rarely practiced.
  • There is not a FDA approved test for men.
  • Clinically it is hard to get men in to get tested.
hpv infection in the us
HPV Infection in the US
  • An estimated 5.5 million people become infected with various types of HPV each year in the U.S.
  • An estimated 20 million people are currently infected with at least one HPV type in the U.S.
  • The “high risk” HPV associated cancers can take years to develop, upwards of 10 to 20 years.
  • Cervical cancer affects younger women more frequently than most other types of cancer.
female invasive cancer incidence washington state 2001
Female Invasive Cancer Incidence (Washington State 2001)

Source: WSDOH, Wash. Comp. Cancer Control, & American Cancer Society

invasive cervical cancer incidence death
Invasive Cervical Cancer Incidence & Death

Source: WSDOH, Wash. Comp. Cancer Control, & American Cancer Society

stage at diagnosis wa 2001

11 of 119 die

91%

survival

32 of 67 die

17 %

survival

55%

survival

52%

survival

16 of 19 die

5 of 11 die

Local

Regional

Distant

Unstaged

Stage at Diagnosis (WA 2001)

Source: WSDOH, Wash. Comp. Cancer Control, & American Cancer Society

Total cases = 216

Number of cases

Stage at diagnosis

risk factors
Risk Factors
  • You do not have to have a lot of sex partners to be exposed.
  • History of multiple sex partners can increase the number of other sexually transmitted diseases
  • Early age at first intercourse
  • Smoking
  • Diet
  • NO Pap screenings
pap smears
Pap Smears
  • Invasive cervical cancer isone of the most preventabletypes of cancer due to the effectiveness of the Pap test.
  • Half of the women who developcervical cancer have not had regular Pap tests.
pap smears1
Pap Smears
  • The cytological changes associated with HPV infection form the basis of the Papanicolau (Pap) smear screening
  • Sampling the cells from the cervix and examining them for signs of malignancy
  • The Pap diagnosis atypical squamous cells of undetermined significance (ASCUS) during cervical screenings
  • This diagnosis indicates cell abnormality but is not sufficient for a definitive diagnosis of a squamous intraepithelial lesion
  • Women who have these abnormalities are referred to get a colposcopic biopsy
treatments for high risk hpv
Treatments for “high risk” HPV

HPV is a long term virus; it is a chronic condition. Procedures target the infected area; treatments do not get rid of the virus.

  • Colposcopic Biopsy – diagnosis for the stage/grade of HPV infection, high grade or low grade
  • LEEP (loop electrocautery excision procedure) – cuts out infected site, most common procedure.
  • Laser – burns off infected site
  • Cryosurgery – freezes off infected site
  • General Surgery – hysterectomy, vulvectomy (in rare cases)
  • Natural Products – stress, immune system boosters
additional risk factors
Additional Risk Factors
  • Women who avoid Pap smears
    • Older women or church go\'ers
    • Self-proclaimed virgins and those who pledge abstinence
  • Truth about Abstinence:
    • 88% of people who take abstinence pledges break them within a year and a half.
    • Those who pledge abstinence are 1/3 less likely to use a condom when they become sexually active
    • More likely to participate in risky sex acts
us compared to world statistics
Worldwide

600,000 new cases of invasive cervical cancer diagnosed annually worldwide.

Cervical cancer kills 270,000 women worldwide.

(2002 statistics)

US compared to World statistics

United States

  • 14,000 new cases of cervical cancer are diagnosed annually in the U.S.
  • In the U.S. 4,000 - 4,500 women die of cervical cancer each year

Source: Science Magazine (2005). High Hopes and Dilemmas for Cervical Cancer Vaccine, Science Magazine, Volume 308, April 29, 2005.

poorer countries have hpv rates
Poorer Countries have > HPV Rates

SOURCE: GLOBOCAN 2002, IARC. Science Magazine, Vol. 308, Issue 5722, pages 618-621 , 29 April 2005

vaccines on the horizon
Vaccines on the Horizon…

SOURCE: Merck and GSK. Science Magazine, Vol. 308, Issue 5722, pages 618-621 , 29 April 2005

challenges with the vaccine
Challenges with the Vaccine
  • Vaccine may have little impact on the cases of cervical cancer
  • Access to a provider and preventive screenings/vaccines will still be an issue
  • Poorer countries have a higher need for the vaccine, but wealthier countries will get it 1st
prevention
Prevention
  • Get regular Pap smears !
  • Don’t smoke
  • Avoid exposure to HPV – use a condom
  • Advocate for greater access to preventive screenings for all populations
  • Live Healthy and Eat Healthy
nutritional support for hpv
Nutritional Support for HPV
  • The following are suggested for protection, as well as support for those who are infected
    • Vitamin C
    • Vitamin A & beta-carotene
    • Folic acid
    • Pyridoxine (B6)
    • Selenium
    • Zinc

Correlation has been found between Copper: Zinc ratio (higher copper and lower zinc) in CIN and cancer patients

therapeutic use of lactoferrin
Therapeutic Use of Lactoferrin
  • Lactoferrin (LF)
    • Iron binding glycoprotein is present in many mucosal secretions including saliva, tears, as well as vaginal and seminal fluids
    • Found in Human breast milk (HLF) as well as bovine milk (BLF)
    • Lf exhibits bacterialcidal and fungicidal activity(particularly Candida species)by depriving bacteria and fungus from iron
therapeutic use of lactoferrin1
Therapeutic Use of Lactoferrin
  • Lf also exhibits anti-viral activity by inhibiting viral binding to glycosamines such as heparin sulphite; it is hypothesized that heparin sulphite mediates the binding of HPV to the host cell
  • Studies have shown that BLF is a better inhibitor than LF and it effectively inhibits HPV-16
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