# ****İrem Aktaş - Papillomaviruses****

Papillomavirus is an 8 kb circular double-stranded DNA virus. Papillomaviruses, non-enveloped and icosahedral, were first discovered to cause warts in cottontail rabbits. The papillomavirus seen in cows is called bovine papillomaviruses (BPV) and seen in humans is called Human papillomaviruses (HPV). Low-risk HPVs are subclinical and cause benign lesions, while high-risk HPVs can cause cancer along with infections. In this chapter, HPV is focused on.

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**1. Features of Papillomaviruses**

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**2. Human Papillomaviruses (HPV)**
*Figure 1: Structure of HPV*

After it was proven that cervical cancer is a sexually transmitted disease, Harold zur Hausen turned to researching the viruses that cause it. Since papillomavirus causes genital warts, he started studies to solve the relationship between HPV and cervical carcinoma. As a result of his studies, he analyzed the HPV-16 and HPV-18 genotypes that are constantly involved in cervical carcinoma.

There are more than 150 subtypes of HPV. Most HPVs manifest as warts. It can be benign or malignant. Benign tumor warts can be cured by freezing and burning treatments. It appears more common in men but can be more dangerous for women. HPV warts in the vagina are difficult to notice and can lead to cervical cancer in the future. HPV-16 and 18 subtypes constitute the majority of cervical cancers. With the discovery of HPV vaccines, cervical cancer death rates have decreased. The prevalence of HPV among healthy people is increasing. According to the latest research, 61.3% of HPV settles in the skin, 41.5% in the vagina, 30% in the mouth and 17.3% in the intestine.

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**2.1 Classification of HPVs**
There are several types of HPV other than HPV-16 and -18. Each type causes different diseases in different tissues.

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**2.2. Transmission of HPVs**
*Figure 2: Transmission of HPV into the cell*

HPV causes cutaneous, anogenital or cervical infection of the epithelium of the skin and mucosa. Transmission through anogenital and cervical infection occurs through sexual contact. In case of a cut on the skin, HPV enters the cells by passing through the physical barrier, the epidermis [Figure 2]. When cell-mediated immunity cannot resist infection, HPV causes infection and manifests itself as warts.

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**2.3. Genome Structure of HPV**
*Figure 3: Genome Structure of HPV*

**Regulatory Elements:**
-Replication Origin
-Early Promoter
-Late Promoter
-Long Control Region

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**2.4. The Life Cycle of HPV**

*Figure 4: The Life Cycle of HPV*

#### In the Earlier Phase, there is entry and transcription processes.

**Entry**
1. The HPV virion first attaches to cells via the ECM and then binds to cells via the HSPG receptor.
2. By endocytosis, HPV enters the cytoplasm within the cell. HPV viral capsids are located inside endosomes in the cytoplasm.
3. The pH level drops in the endosomes and the L2 capsid protein emerges. The L2 capsid triggers the breakdown of the endosome membrane.
4. Since HPV is a small virus, it enters the nucleus through the pores.
5. Viral capsids get rid of capsid proteins and the viral genome is exposed.

**Transcription**
1. Cellular RNA polymerase II transcribes RNAs early in the LCR.
2. Viral RNAs are alternatively spliced into multiple mRNAs.

#### In the Late Phase, there is transcription and genome replication processes.

**Transcription**
1. Late RNAs are transcribed from promoters in the LCR.
2. Viral RNAs are alternatively spliced and multiple mRNAs are formed.

**Genome Replication**
*Figure 5: Phases of HPV Genome Replication*

1. Establishment:
* After HPV infects keratinocytes in the epidermis, 50-100 copies of the viral genome are produced per cell.
2. Maintenance:
* Viral genomes or episomes are copied simultaneously with cellular DNA replication.
3. Amplification:
* Infected cells differentiate and migrate to the upper layers of the epidermis.
* Cells that pass into the upper layers are replicated until there are almost 1000 copies per cell.
* During replication, L1 and L2 are synthesized and accumulated.
* The amplified viral DNAs are packaged into new viral particles.
* During packaging, E6 and E7 control the cell cycle. It sends cells into S phase and amplifies the viral genome of cells that can exit the cell cycle. 
*Figure 6: Initiation of HPV Genome Replication. E1 binds to ori at the LCR and interacts with E2 to initiate viral genome replication.*