Human Papillomavirus Infection Treatment and Prevention

HPV infection Cancer, a growing conundrum in the world with profound abilities to disarm an individual's strength and thrive on its own will to belittle the immune system. Such dominance is exerted with the aid of an external agent such as Human Papilloma Virus (HPV).

What is HPV?
HPV is a double stranded Deoxyribonucleic Acid (DNA) virus that affects mucosal and cutaneous epithelial cells. They have a non-enveloped icosanearal capsid, approximately 8 kb (kilo base pair) in length with a diameter of 52-55nm.
There are more than 100 types of HPV including 13 high risk HPV (hrHPV) and they result in benign and malignant epithelial lesions or warts in men and women. Of which, two most common hrHPV genotypes 16 and 18 cause around 70% of cervical cancer. A number of them infect cervix and are associated with cervical cancer. Noticeably, they can also cause anogenital cancers and oropharyngeal cancers.

What does HPV affect mean?
HPV infections bring about 6,30,000 new cases every year and 83% of them cause cervical cancer. Other cases include head and neck along with anogenital cancer. It has also engulfed 60,000 men worldwide in 2018. Worldwide cervical cancer is the 4" highest cancer among women.

India witnesses nearly 1,22,844 new cervical cancer cases every year. It is the second most common cancer in Indian women and more so affects women between the age 15-44 years. There are 23 cases of HPV infection per 1000 women in India in a year. This is higher than the global burden that causes 14 new cases per 1000 women in the world."

What is the link between HPV and cancer?
Genes of HPV are considered as a tumor DNA, so to speak for its ability, to cause cancer. It is classified into high risk or oncogenic type or low risks or nononcogenic type. HPV type 16, 18, 31, 33, 35, 39, 45, 51, 52, and 58 are considered as oncogenic and account for cervical, vaginal, vulvar and anal cancer. HPV type 6, 11, 40, 42, 43, 44, and 54 are non-oncogenic and can cause genital warts.

Infection spreads through 'skin to skin contact and through sexual intercourse. The virus enters the host and establishes itself using different proteins that it encodes. It has eight Open Reading Frames (ORF's) that consists of proteins required for its life cycle to enhance their numbers.

ORF is divided into three regions:
Early (E) region-Encodes proteins E1 to E7 that assist in replication of HPV.
' Long (L) region-Encodes for structural proteins that are required for virus assembly.
' Long Control Region (LCR)- Contains cis elements required for replication and transcription.

E1 and E2 proteins are required to identify the origin of replication. E1 works as a helicase and unwinds DNA. Interaction of E1 with replication protein A, causes stabilization of single stranded DNA. E2 protein helps in the process of dimerization with E1 and regulates transcription.
Although an early protein, E4 expressions increases later in the life cycle. It helps in expression of late genes, required for virion assembly. E4 also disrupts intermediate filaments, cornified cell envelope so, newly synthesized HPV is then released from the cell.
E5 is not found in every HPV virus, it helps proteins E6 and E7 to raise their functional activity.
E6 binds to tumor suppressor protein p53 and degrade them by recruiting protein ligase. E6 also binds to apoptotic proteins as well as DNA replication and repair factors to degrade them.
E7 binds to retinoblastoma proteins p105Rb, p107 and p130 and lead to inhibition of these tumor suppressor proteins.
Major structural proteins of HPV are encoded by L1 protein. Formation of pentamer capsids and complex loops of the same, depend on L1 protein.
L2 causes interaction of virions to the cell receptor and helps virion uptake by cell. It guides a virion towards nucleus particularly to replication centers.
Proteins of LCR region are required for transcription, differential expression of genes, switching from early to late genes in order to activate them and feed back control of gene products. However all these roles are deregulated when cells attain malignancy.

Risk factors associated with HPV
- Multiple sexual partners have been the primary reason for transmission of HPV. An older sexual partner might have already come across HPV infections. Hence such factors makes a person more prone to acquiring HPV.
- Age is a risk factor associated with HPV, as young adults between the age of 15-25 years fall prey to it.
- It is also believed that 75% of new cases every year arise between in this age group.
- Women are prone, for showing poor adoptive immune response. Also young women go through biological changes that involve squamous metaplasia of cervical epithelium, a risk factor of HPV.
- Untreated pre cancerous lesions can become invasive and malignant in nature.
- Substance abuse, cigarette smoking and alcohol intake elevate the chances of developing precancerous lesion in an HPV infection.
- If an individual already hosts the infection, then cooccurrence of sexually transmitted infections such as Chlamydia Trachomatis and Herpes Simplex Virus, plays a major role in oncogenic pathways.

What is the diagnosis method for HPV?
Polymerase Chain Reaction (PCR) PCR is the most trusted method to detect HPV, as it targets the specific genes and allows its amplification. In PCR, multiple copies generated after number of cycles allows more sensitive and specific detection. The regions are targeted using specific set of primers and probes. Mostly degenerate primers assist in detection of a large number of HPV types. Although primers targeting the L1, E1 and E6 are utilized, L1 region is particularly beneficial for consensus primes and allow detection of mucosal HPVs. Primers like the MY09/11 are specific for such amplifications. Epidermodysplasia Verruciformis (EV) occur because of HPV resulting a mutation in chromosome number 17. Using primers such as the FAP59/64 gives and added advantage, as it allows detection of EV HPVs along with cutaneous HPVs. Nested PCR and quantitative PCR types are used in this detection.

The PCR analysis is performed using any of the mentioned set of primers to identify the viral particles. Usually specimens like genital swabs and scrappings from the suspected areas of infection is subjected to PCR.

Biopsy The sample is generally taken from the abnormal areas hence biopsy forms a part of colposcopy; technique involves using a low powered microscope to examine the cervix, vagina and also vulva. Biopsy sample are tested to check if they show dysplasia or cancer. This further guides for treatment.

PAP Screening A PAP smear taken from the affected area which directs on pre malignant and malignant changes that occur in the lesions. Hence, this test forms an important parameter to confirm and monitor HPV infections.

Can you get the HPV vaccine?
Vaccination takes a step towards prevention and raises the potential to fight HPV. The vaccine targets HPV types 6, 11, 16 and 18. Non-infectious virus like particles are made using recombinant DNA technology. The L1 protein is expressed in yeast, that form the empty

shells but is deprived of the genetic material and only have the outer L1 protein (antigen). Also recombinant vaccinia virus is used that expresses the HPV 16 and 18 E6 and E7 genes, to reach out to prevent maximum occurrence. The E6 and E7 proteins are mutated to stop their tumor suppressor binding activity.' Nearly 80 countries in the world have introduced HPV vaccine to its citizens

India has taken its initiative to cure HPV with all its might. The vaccination programme is introduced which is yet to make its place formally in the country. Quadrivalent covering HPV types 6, 11, 16 and 18, bivalent type covering HPV types 16 and 18 are the usual forms available

HPV is a transmissible viral infection, reducing the body's ability to face cancer and bring about the downfall. The risk factors associated are completely in an individual control and this assisted with frequent check will help in early control of HPV.