HPV, Warts, and Cervical Cancer

Question 1

Unique features of HPV structure and life cycle

Answer 1

• dsDNA virus, icosahedral shape
• Non-enveloped
• 50nm in diameter
• DNA produces 8-10 proteins
  
  • 6-8 expressed early in infection
  • 2 capsid proteins expressed late in infection
  • Proteins commit cell to replication of viral DNA + inhibit cell apoptosis
    
    • E6 binds p53 –> targeting for degradation
    • E7 binds pRb –> increases protein synthesis for DNA replication + deregulates cell cycle
• 200 serotypes distinguished by DNA –> different capsid proteins

Question 2

HPV infection

Answer 2

• Only infects undifferentiated proliferating basal layer cells (stem cells)
• PVs are epitheliotropic and only infect epithelium of:
  
  • Skin
  • Anogenital tract
  • Oropharyngeal mucosa
• Infection begins with virus invading basal cell, usually after trauma
  
  • Transcription, replication, assembly linked to differentiating layers of epithelium
  • Capsid genes transcription, translation, and virus release only occur at epithelial surface

Question 3

Low-risk HPV genotypes and associated diseases

Answer 3

• HPV 6 + 11
• Associated diseases:
  
  • Anogenital wart/condyloma acuminata
    
    • One of most common STDs, highly contagious
  • Respiratory papillomatosis
    
    • Warts form on larynx or other areas of respiratory tract
    • Can kill people if it blocks respiratory tract

Question 4

High-risk HPV genotypes

Answer 4

• HPV16
  
  • 50% of cervical cancers
• HPV18
  
  • 20% of cervical cancers
• HPV31
  
  • 25% of cervical cancers when combined with HPV 33 & 45

Question 5

HPV and association with cancers

Answer 5

• All cervical cancers related to previous high risk HPV infection
• 99% of HPV-associated cervical cancers arise within transformation zone (immature metaplasia between original and current squamocolumnar junction)
• 25% of head and neck cancers associated with HPV
  
  • Arise from squamous cells of mouth and throat region
  • 4th most frequent cancer worldwide, 6th in US
  • Less than 50% survival rate - not improved much for decades
  • Oropharynx most frequent anatomical site for HPV-associated cancer incidence
• Also associated with:
  
  • Squamous cell cancer of vulva and vagina (33%)
  • Carcinoma of the penis (50%)
  • Anal cancer (66%)
• Up to 5% of world cancer burden related to HPV infection

Question 6

HPV oncoproteins and cellular targets

Answer 6

• E6 protein
  
  • Binds p53
  • Targets it for degradation
  • Inhibits cell senescence
• E7 protein
  
  • Binds pRb
  • Releases E2F transcription factor
  • Increases synthesis of DNA replicaiton proteins
  • Deregulates cell cycle

Question 7

Diagnosis of HPV-associated lesions

Answer 7

• Inspect skin, mouth, throat, vagina, penis, anus, hands, and feet - look for warts
• Pap smear
• HPV testing
• Colposcopy

Question 8

Pap Smear

Answer 8

• Papnicolau smear test (Pap smear, Pap test, cervial smear, smear test)
• Gynecological screening test used to:
  
  • Identify premalignant and malignant processes in exocervix
  • Detect cytologic evidence of HPV infection and tissue abnormality

Question 9

HPV testing

Answer 9

• Genotyping and HPV detection have been crucial in diagnosing and prognosing HPV-associated diseases
• PCR technique has been common method to detect HPV DNA in specimen
• Recently other tests using various approaches developed for more accurate/comprehensive diagnosis/prognosis of HPV infection:
  
  • Hybrid Capture II
  • PreTect HPV Proofer
  • Roche Linear Array

Question 10

Colposcopy

Answer 10

• If Pap smear is abnormal –> next step colposcopy
• Using binocular instrument (colposcope) to look closer at cervix
• Many times combined with biopsies for further pathological examination

Question 11

HPV vaccines and limitations

Answer 11

• Limitations include:
  
  • Lack of therapeutic effect; VLPs only induce antibody response
  • Only reduce HPV in future generations
  • Do not cover HPV genotypes causing ~30% cancers
  • Inability to reach all target vaccines due to high cost (>$300)
  • Opposition by some social, religious groups

Question 12

Gardasil vaccine (FYI)

Answer 12

• Manufacturer: Merck
• Construction: VLPs of L1 protein made in yeast with aluminum adjuvant
• Serotype coverage: HPV 6/11/16/18
• FDA approval: 2006

Question 13

Cervarix vaccine (FYI)

Answer 13

• Manufacturer: GSK
• Construction: VLPs of L1 protein made in insect cells with AS04 adjuvant
• Serotype coverage: HPV 16/18
• FDA approval: October 2009