Human Papilloma Virus Yasir Waheed, PhD

The plurality of HPV genotypes is associated with its ability to cause a wide spectrum of epithelial proliferative lesions. The global burden of HPV associated diseases is quite high, and is estimated to be about 5.17 per cent of total cancer burden. Among the HPV-associated diseases, cervical cancer which is the second most common cancer among women around globe.

On the basis of their association with disease types, papillomaviruses are classified into high-risk (HR) and low-risk (LR) types. HR-HPV types (HPV 16, 18, 31, 35, 39, 45, 51, 52, 56, 59, 66, 68, 69 and 73) are often associated with high grade lesions and invasive cancer, whereas the LR-HPV types (HPV 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81) are mainly found in low grade lesions, genital or skin warts. There are about 15 high-risk HPV types have been described, which contribute to about 100 per cent to the HPV-attributable cancer burden worldwide. Among them, HPV 16 and HPV 18 are the most prevalent oncogenic genotypes as two together are responsible for more than 80 per cent of total HPV associated cancerous lesions.

Papillomaviruses are small, approximately 52-55nm in diameter. They are non-enveloped, icosahedra particles. This shape is made up of 12 pentameric and 60 hexameric capsomers.  Their capsid is composed of two proteins, a major (L1) and minor (L2). SEM image of a Human Papilloma Virus and a computer model showing the structure of the virus.

They are DNA viruses.   HPV is part of the family known as Papovaviruses, which was named for it’s three main members: PApillomavirus, POlyomavirus, and simian Vacuolating Agent. They are found in many vertebrates, and exhibit high species specificity. This family contains two genera of oncogenic viruses, Papilloma and Polyoma viruses. The Papillomavirus’ genome is circular, d/s DNA approximately 8,000bp in size. Many of the HPV genomes have been sequenced and have a genetic organization similar to that of HPV-16, one of the oncogenic strains.

Expression of the Papillomavirus genome is very complex and not well understood, because it has at least seven promoters, exhibits many alternative splicing patterns, and has an unknown link to cell differentiation.

HPV Infection Outcomes E6 and E7 interact with many cellular proteins, which influence the outcome of infection.

Figure 17-33. How DNA damage arrests the cell cycle in G1 Figure 17-33. How DNA damage arrests the cell cycle in G1. When DNA is damaged, protein kinases that phosphorylate p53 are activated. Mdm2 normally binds to p53 and promotes its ubiquitylation and destruction in proteasomes. Phosphorylation of p53 blocks its binding to Mdm2; as a result, p53 accumulates to high levels and stimulates transcription of the gene that encodes the CKI protein p21. The p21 binds and inactivates G1/S-Cdk and S-Cdk complexes, arresting the cell in G1. In some cases, DNA damage also induces either the phosphorylation of Mdm2 or a decrease in Mdm2 production, which causes an increase in p53 (not shown).

Can HPV Cause Other Types of Cancer? A 2005 study entitled “Sensitive detection of Human Papillomavirus in cervical, head/neck, and schistosomiasis-associated bladder malignancies” found that: “Virtually all tested cervical cancers and schistosomiasis-associated bladder cancers, and a plurality of head/neck cancers are associated with HPV DNA in the tumor.” HPV DNA was present in 35%of head and neck cancers analyzed (253 samples). HPV DNA was present in 98%of cervical cancers analyzed. HPV DNA was present in all 27 samples of schistosomiasis-associated bladder cancer analyzed. In another study, HPV DNA was found in 25 of 29 samples of breast carcinoma. Strains 11 and 6 were most prevalent.

The Bad News Cervical cancer is the second leading cause of cancer death among women world wide. An estimated 75%of women in the U.S. will be exposed to HPV at some point in their lives.

…And Now The Good News 70% of women infected with HPV clear the infection through natural means within two years. It may take 10 to 15 years for an HPV infection to develop into cancer. Vaccines are currently in development against oncogenic strains.

Conventional therapies Even after establishment of causal relationship between HPV and cervical cancer, currently, presence or absence of HPV does not have any impact on deciding the treatment; the strategies are primarily anti-cancer and not anti-viral. Several therapies are available for treatment of HPV-associated diseases. These treatment strategies are ablative in nature and aim to remove the lesion rather than specifically targeting the HPV infection. These treatments though effective are applicable only when the lesion is visible and does not necessarily eliminate HPV infection. Some of these procedure are also associated with significant morbidity such as profuse watery discharge, bleeding, cervical stenosis (narrowing) and in some cases cervical incompetence and pelvic infection. Even though these treatment modalities are effective, all of them are associated with considerable degree of recurrence which ranges upto 10 per cent of the cases.

Alternative Therapies Cytotoxic agents: Though scissor excision is the most preferred methods for genital warts, topical preparations of cytotoxic compounds like Podophyllin or Trichloroacetic acid are also utilized in USA and Europe. Similarly 5-Fluorouracil is also available but with very limited use for external genital lesions as it generates strong inflammatory reaction. Use of Podophyllin and 5-Fluorouracil is contra-indicated in pregnancy. Most of these therapies show no or inconsistent antiviral dose response against HPV. Recently, two most common anti-cancer agents for treatment of many cancers including cervical cancer, arsenic trioxide (As2O3) and carboplatin have been shown to target two most important transcription factors, AP-1 and NF-κB respectively that play a critical role in expression of HPV oncoprotiens E6 and E7.

Immunotherapy Interferons (IFNs) are the only antiviral drugs approved for the therapy of benign HPV related lesions. While IFN-α, IFN-β and IFN-γ have all been tested against condyloma acuminata, most information is available on IFN-α which appears efficacious via a number of routes of administration, schedules and dosages with an acceptable safety profile. Success with IFN-α therapy, in terms of reduced recurrence rates of condylomas was reported from studies in which all visible lesions were surgically removed with subsequent administration of subcutaneous local IFN-α .

Photodynamic therapy (PDT) PDT is a new treatment for a wide variety of malignancies and premalignant dysplasias, as well as some non-cancer indications. Therapeutic response to PTD is achieved through the activation of non-toxic photosensitiser located within neoplastic tissue, using visible light tuned to the appropriate absorption band of the photosensitiser molecule. This produces cytotoxic free radicals such as singlet oxygen, which result in local photooxidation, cell damage and destruction of the tumour cells that may induce bystander effect and activate host immunity.