ROLE OF HUMAN PAPILLOMA VIRUS IN CERVICAL CANCER

ROLE OF HUMAN PAPILLOMA VIRUS  IN CERVICAL CANCER

 Human papillomavirus (HPV) is the most common virus causing sexually transmitted infection (STI) and viral infection of the reproductive tract. Human papillomavirus infection can be transmitted via both sexual and nonsexual contacts. Human papillomavirus penetrates the body through the skin and epidermis that cause injury in mucous membranes and cause skin abrasions. Human papillomavirus is a double-stranded closed circular DNA virus with the capacity to incorporate in the human DNA. Infection caused by HPV is known as a public health problem for its role as a sexually transmitted disease and also as a dangerous factor in the pathogenesis of various cancers, crucially cervical cancer. Cervical cancer is a category of cancer that occurs in the cells of the cervix - the lower part of the uterus that connects to the vagina. Cervical cancer is the most ordinary cancer of women worldwide. There are over 150 different types of Human papillomavirus.  Not all types of Human papillomavirus are harmful. Some have a higher risk of causing cancer. HPV 16 and HPV 18, as compared to other papillomas are the two high-risk viruses that are identified to cause about 70% of cervical cancer. HPV 16 and 18 positive LSIL (Low-grade squamous intraepithelial lesion) are more likely to progress to cervical cancer than LSIL containing other HPV genotypes. LSIL shows the common abnormal result on a Pap test. It is also known as mild dysplasia it identifies that your cervical cells show mild abnormalities.

Ø  Cervical cancer is cancer arising from the cervix. It is due to the abnormal growth of cells that have the ability to invade or spread to other parts of the body.

Ø  Cervical cancer is the fourth most frequent cancer in women with an estimated 570,000 new cases in 2018.

Ø  India recorded the highest estimated number of cervical cancer deaths in 2018 contributing to 97,000 cases and 60,000 deaths.

Ø  All women are at risk for cervical cancer. It occurs most often in women over the age 30. Long-lasting infection with certain types of human papillomavirus (HPV) is the main cause of cervical cancer.

HISTORY

Ø  In 1976, Harald Zur Hausen published the hypothesis that human papilloma virus plays an important role in the cause of Cervical cancer. 

Ø  In 1983 and 1984, Zur Hausen and his collaborators identified HPV16 and HPV18 in  Cervical cancer.

Ø   In 1983, Zur Hausen published evidence that HPV-11 was present in three out of 24 cervical cancer samples. 

RISK FACTOR OF HPV INFECTION

Ø  Most sexually active men and women will contract the HPV virus at some point during their lifetime.

Ø  HPV can be spread through oral, vaginal, or anal sex.

Ø  It can result in genital warts and some types of cancer.

Ø  The virus, which spreads through skin-to-skin or other intimate contacts, will often go away on its own, although certain strains can cause cervical cancer.

Ø  Sometimes, HPV can be transmitted during birth to an infant causing genital or respiratory system infections.

Ø  There is no cure for HPV but safe and effective vaccinations are recommended at the age of 11 to 12 years.

Ø In most cases, HPV infections won’t show symptoms and will clear up on their own. But two strains, HPV-16, and HPV-18 can cause precancerous cervical lesions and cervical cancer.

Symptoms of cervical cancer

Cervical cancer is generally asymptomatic until it has reached a later stage. Advanced symptoms of cervical cancer includes:

Ø   irregular bleeding, bleeding between periods, or abnormal vaginal bleeding after sex.

Ø  leg, back, or pelvic pain

Ø  vaginal pain

Ø  foul smelling discharge

Ø  weight loss

Ø  loss of appetite

Ø  fatigue

Ø  a single swollen leg

 

HPV GENOME

 

CORRELATION BETWEEN HPV AND CERVICAL CANCER

An HPV infection does not necessarily mean that individuals would contract cervical cancer, even with infection of high-risk types, which are associated with cancer only because they are more prone to cause cell proliferation. Integration of HPV’s genome into the host is connected with neoplasia--unusual growth of cells. This could be caused by the proliferation of cells and subsequent loss of DNA repair mechanisms, which could lead to further accumulation of chromosomal mutations.

The two genes highly associated with the carcinogenic activity are E6 and E7. It is commonly thought that these work by interaction with two different target genes. The mechanism of E7 is well-established. It is hypothesized that E7 binds to the retinoblastoma protein (pRb), which inhibits its normal function. During typical cell function, pRb binds to E2F, which is a transcription factor that can activate oncogenes that contain sequences for cyclin E and c-Myc proteins. Cyclin E is needed to advance the cell to mitosis and c-Myc is needed for mitosis. If the production of these proteins is uninterrupted by pRb, then the cell continues to divide unregulated. The binding of E7 to pRb also promotes the degradation of pRb by the cell’s proteasomes, which are large protein complexes that degrade proteins. Both of these outcomes result in cell proliferation. The mechanism for E6 is simpler. The protein E6 binds to p53 and inactivates it. The gene p53 has several roles that regulate the cell cycle, induce apoptosis, promote DNA repair, and prevent tumor growth. Inhibition of p53 would stop these functions and could cause unregulated cell proliferation and cancer.

Although E6 and E7 genes are associated with carcinoma of HPV, they are not the sole cause. There are detectable levels of E6 and E7 in non-cancerous infections. The integration of the HPV genome into the host genome is connected with cancer. This could be due to the loss of E2 during integration into the host genome. E2 encodes proteins that regulate viral gene expression if E2 does not regulate the expression of E6 and E7, then the cell goes can proliferate and cause cancer. It should be noted that a nonsense or missense mutation of E2 could also cause the same problem.

HPV mechanism in Cervical cancer

TREATMENT OF HPV INFECTION 

Ø  There is no standard treatment for HPV or cervical cancer. The CDC has stated that 90% of HPV infections can clear up in two years.  It is possible that it may not be gone, but just at low levels that cannot be detected.

Ø  HPV were detected, the individual should be monitored to ensure the infection does not quickly manifest into neoplasia. In the case of neoplasia, there are some surgical options, which include ablation or excision.

Ø  These options are not always the most efficient method, because they can leave diseased tissue or remove healthy along with diseased tissue.

Ø  There can also be some corresponding obstetric complications. Often the success of these treatments depends on the follow-up.

Ø  There are some other alternative options such as therapeutic vaccines and anti-viral medications.

Therapeutic Vaccines

Therapeutic vaccines can have many different targets, but most aim to cause cytotoxic T-lymphocyte (CTLs) to respond in order to clear the established infection. These CTLs are usually designed to target viral oncogenes antigens of the most frequent high-risk HPVs. One method is using a prime-boost strategy.  This entails priming with plasmid or viral vector DNA followed by a different viral vector encoding the immunogen. This method has an improved response in animal models but has problems with the generation of CTL activity because of inhibition by T-helper 2-driven humoral immunity.

Antivirals

Three antivirals that can be used to treat HPV are cidofovir, imiquimod, and interferon. Cidofovir, an acyclic nucleoside phosphonate, is a broad-spectrum antiviral. It works by inducing apoptosis in infected cells. This may happen by lowering the levels of E6 and E7 and increase the levels of p53 and pRb, which suppress tumor growth.  It is commonly used intravenously and can be used for immunosuppressed individuals. Interferon is an antiviral immune response that either induces dsRNA endonuclease or acts as eIF2 kinase.

CONCLUSION

Ø  There is important heterogeneity in cervical cancer screening frequency and coverage. Despite low awareness of HPV infection, the majority of respondents would recommend or are ready to receive the HPV vaccine, but the cost could prevent its acceptability.

Ø  This study adds new knowledge to the known pathogenic pathways of HPV and substantiates the oncogenic role of HPV in Cervical Cancer.