The HPV enters through the minor or micro abrasion in the basal layer of the epithelium (stratum germinativum). This selective infection of basal layer occurs due to its preferential binding with heparin sulfate proteoglycan (HSPG) on the basement membrane which is exposed on minor trauma or abrasion. Once the virus enters, the infectious cycle of the virus is dependent upon the differentiation program of the squamous epithelial cells. The replication of virus DNA occurs as the basal cell differentiates and progresses towards the surface of the epithelium. This is evidenced by the presence of viral capsid proteins, viral DNA and viral particles only in the terminally differentiated cells.

Replication of virus is almost non-productive at the basal layer. It establishes itself as a low copy number episome, and with the help of host cell machinery viral DNA is synthesized once per cell cycle.

In the differentiated suprabasal layer, the pattern of viral DNA replication gets switched over to the rolling circle mode which leads to synthesis of high copy number of DNA, capsid proteins and assemble of virions (Fig.1).

Fig1. HPV infection of epithelium

When HPV replication starts, transcription of E6 and E7 occurs. The function of E6 and E7 is to destabilize the cell growth regulatory pathway and also to alter the cellular environment to enhance viral replication in a terminally differentiated cell.

The tumor suppressor gene, p53 and retinoblastoma gene product pRB are the two main cellular proteins responsible for cell cycle regulation.

E6 of high-risk HPV types has high affinity to bind p53 protein and causes rapid degradation. It forms complex with p53 with the help of cellular ubiquitin ligase E6AP. This ubiquitylation leads to degradation of p53 protein. It also downregulates p53 by targeting the co-activator of p53, CBP/p300. As a consequence, normal functions of p53 like cell cycle arrest at G1, apoptosis and DNA repair gets arrested, thereby facilitating the process of oncogenesis.

E7 binds to the hypophosphorylated form of Rb. This binding breaks the complex of pRb and cellular transcription factor E2F-1, leading to the release of E2F-1. This leads to transcription of those genes whose products are essential for cell cycle progression and DNA replication, thus leading to cellular proliferation and enhanced cellular DNA synthesis.

E6 and E7 proteins of low-risk HPV types have low affinity to bind with p53 and pRb proteins, respectively. Whereas E6 and E7 of high-risk HPVs like HPV16 and HPV18 are responsible for the immortalization and transformation of the infected cells.

Pathogenesis of Cervical Cancer

 HPV infection of the genital tract is self-limiting in most of the cases. Clearance of virus usually occurs within 12 months. Persistence of virus is more commonly seen with the high-risk HPV types; although it has also been observed with some low-risk HPVs. Longer the virus persists chance of clearance becomes less. Amongst the persistent infection, only some develop CIN3 and amongst the CIN3, only some develop invasive cancer.

The risk of development of invasive cancer depends on several factors:

i. Persistence of virus,

 ii. infection with high-risk HPV type, and

 iii. variant of HPV within the virus type.

Persistent infection with a high-risk HPV type is the most important risk factor for development of invasive cancer. Early age of sexual debut, multiple partners, chronic inflammation of genital tract, immunosuppression and smoking are the other risk factors for development of invasive cancer.

Molecular Pathogenesis

 Integration of Viral DNA

 • Integration of HPV DNA occurs mostly with the high-risk HPV types. The rate of integration varies with different HPV types. Most of the lesions produced by HPV18 and HPV45 show viral DNA integration; whereas in HPV 16 infection, this is seen in more than 50% lesions.

• Integration of HPV DNA stabilizes the high expression of E6 and E7; the two oncoproteins responsible for the transformation.

• Integration of viral DNA is associated with more severe lesions (85% in invasive cancer vs 16% in CIN3, 5% CIN2 and none in CIN1).

• Integration of viral DNA is associated with deletion of a large part of viral genome which includes deletion of E1 and E2 genes but retaining E6, E7 and LCR. E2 being a transcriptional repressor, deletion of E2 removes the check on transcription of E6 and E7. This in turn leads to high level transcription of E6 and E7.

Activation of telomerase: E6 gene activates telomerase (hTERT). This activation leads to severe dysplasia and cervical cancer.

Aneuploidy and genomic instability due to E6 and E7 in infection with high-risk HPV type also contributes towards development of invasive cancer.

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مواضيع ذات صلة

Epidemiology Human Papillomavirus

Clinical Syndromes of EBV

EBV Life Cycle

Epstein–Barr virus

Treatment of Cytomegalovirus

Diagnosis of Cytomegalovirus

Clinical Manifestations of Cytomegalovirus

The Viral Genome

Human Immunodeficiency Virus

Viral Pathogenesis

VIRUSES

Human Cytomegalovirus