HUMAN PAPILLOMA VIRUS

1. Viral Structure:

   • HPV is a non-enveloped virus with an icosahedral capsid composed of two structural proteins, L1 and L2. The viral genome is about 8,000 base pairs and contains early and late coding regions.
   • The early region (E1-E7) encodes proteins responsible for viral replication and transformation. The late region (L1 and L2) encodes structural proteins for the viral capsid.

2. Infection Mechanism:

   • HPV infects the basal layer of stratified squamous epithelium through microabrasions or breaks in the skin or mucous membranes.
   • The virus uses the L1 protein to bind to heparan sulfate proteoglycans on the surface of basal keratinocytes, followed by internalization via receptor-mediated endocytosis.
   • Once inside the cell, HPV replicates episomally (extrachromosomal), with the viral genome being maintained in the nucleus of the infected cells.

3. Viral Replication and Oncogenesis:

   • HPV replicates in concert with the differentiation of infected epithelial cells. As cells move upwards through the layers of the epithelium, the virus utilizes the host cell machinery for genome replication and assembly.
   • High-risk HPV types, particularly HPV 16 and HPV 18, produce two key oncoproteins: E6 and E7. These oncoproteins disrupt normal cell cycle regulation:
     • E6 promotes degradation of the tumor suppressor protein p53, preventing apoptosis.
     • E7 binds to and inactivates the retinoblastoma protein (pRb), leading to uncontrolled cell proliferation.
   • Persistent infection with high-risk HPV types results in integration of the viral DNA into the host genome, leading to the accumulation of genetic mutations and progression to high-grade intraepithelial lesions and eventually cancer.

Clinical Manifestations:

1. Low-Risk HPV (e.g., types 6, 11):

   • Responsible for benign lesions such as condyloma acuminata (genital warts) and laryngeal papillomatosis.
   • These HPV types generally cause non-cancerous warts on the anogenital and respiratory mucosa.

2. High-Risk HPV (e.g., types 16, 18, 31, 33):

   • Associated with precancerous lesions and malignancies, including:
     • Cervical cancer: HPV infection is the primary cause of virtually all cases of cervical cancer. Persistent infection with high-risk types leads to cervical intraepithelial neoplasia (CIN), which can progress to invasive carcinoma.
     • Oropharyngeal cancer: HPV, especially type 16, has been linked to cancers of the oropharynx, including the tonsils and base of the tongue.
     • Anal, vulvar, vaginal, and penile cancers: These cancers are also associated with persistent HPV infection.

HPV-Related Diseases:

1. Cervical Intraepithelial Neoplasia (CIN):

   • CIN1: Mild dysplasia (low-grade squamous intraepithelial lesion) that often regresses spontaneously.
   • CIN2 and CIN3: Moderate to severe dysplasia (high-grade squamous intraepithelial lesion) that have a higher likelihood of progressing to invasive cervical cancer if left untreated.

2. Cervical Cancer:

   • Most commonly associated with HPV 16 and 18, which together account for approximately 70% of cervical cancer cases. HPV 31 and 33 also contribute to a smaller percentage of cases.
   • Cancer development typically occurs after years of persistent infection, with precursor lesions progressing from CIN to carcinoma in situ and ultimately invasive cancer.

3. Oropharyngeal and Anogenital Cancers:

   • HPV 16 is most frequently associated with cancers of the oropharynx, including the tonsils and base of the tongue.
   • HPV 16, 18, 31, and 33 are also linked to cancers of the anus, vulva, vagina, and penis.

Diagnosis:

1. Pap Smear (Papanicolaou test):

   • A screening tool used to detect cytological abnormalities in cervical cells, indicative of HPV infection or precancerous changes.
   • Abnormal Pap smear results, such as ASC-US (atypical squamous cells of undetermined significance) or LSIL/HSIL (low-/high-grade squamous intraepithelial lesion), often prompt further diagnostic evaluation. Pap smear should be done every 3years from 21years of age.

2. HPV DNA Testing:

   • Direct detection of high-risk HPV types from cervical samples. HPV DNA testing is used for primary screening, co-testing with the Pap smear, and follow-up after abnormal results. Recommended every 5years from 31years of age.

3. Colposcopy and Biopsy:

   • Colposcopy provides a magnified view of the cervix, allowing visualization of abnormal areas that may require biopsy for histopathological evaluation.

HPV Vaccination: Cervarix(16,18), Gardasil(6,11,16,18), Gardasil 9.

1. Prophylactic HPV Vaccines:
   • The available vaccines (e.g., Gardasil 9) protect against the most common high-risk HPV types (16, 18) as well as low-risk types (6, 11).
   • Vaccination is recommended for both males and females, ideally before the onset of sexual activity, to prevent the development of HPV-related cancers and genital warts.
   • Gardasil 9 covers nine HPV types: 6, 11, 16, 18, 31, 33, 45, 52, and 58.
2. Vaccination Schedule:
   • Typically administered in two or three doses depending on the age of the individual. Two doses recommended from 9-15years of age i.e 0 and 6months. Three doses recommended from 15-26years of age i.e 0,1 and 6months.

Management of HPV-Related Lesions:

1. Cervical Precancerous Lesions (CIN):

   • Observation: CIN1 often resolves spontaneously, especially in younger women.
   • Surgical intervention: CIN2 and CIN3 may require excision via LEEP (Loop Electrosurgical Excision Procedure) or cold knife conization to prevent progression to cancer.

2. Genital Warts:

   • Treatments include cryotherapy, topical agents (e.g., imiquimod, podophyllotoxin), or surgical excision.

3. HPV-Related Cancers:

   • Surgery, radiotherapy, and chemotherapy are mainstays of treatment, depending on the stage of the cancer.

Natural History of HPV Infection:

• Transient Infection: In most cases, HPV infections are transient and 95% are cleared by the host’s immune system within 1-2 years, particularly in young individuals.
• Persistent Infection: In a minority of cases, particularly with high-risk HPV types, the infection persists, leading to the development of precancerous lesions and eventually cancer.

Prevention:

1. Safe Sexual Practices: The use of condoms reduces, but does not entirely eliminate, the risk of HPV transmission.
2. Regular Screening: Pap smears and HPV testing play a critical role in detecting precancerous changes before they progress to cancer.
3. Vaccination: Prevents infection with the most oncogenic HPV types, significantly reducing the incidence of cervical and other HPV-related cancers.