Human papillomavirus (HPV)

What is Human papillomavirus (HPV)?

HPV, or human papillomavirus, is an epithelial, spherical DNA virus that is highly stable in nature. HPV relies on the host for replication, transcription, and translation, and exists in a free or fused state within the cell, but does not appear in the blood and saliva. It can cause squamous epithelial hyperplasia of human skin and mucous membranes, manifesting as common warts, genital warts (genital warts), and some types are potentially carcinogenic. HPV can infect humans through direct or indirect contact with contaminated objects or sexually transmitted through sexual transmission. The virus is not only host-specific, but also tissue-specific, and can only infect human skin and mucosal epithelial cells, causing multiple papilloma or warts and proliferative lesions of the genital tract epithelium. Almost 100% of cervical cancers are caused by human papillomavirus infection, and cervical cancer is the fourth most common malignancy in women worldwide.

Human papillomavirus structure

HPV consists of a viral protein capsid and a core single copy of the viral genomic DNA. The viral capsid is composed of two proteins, L1 and L2: L1 forms the pentamer, L2 is located in the middle of the pentamer, and 72 pentamers form an icosahedral symmetrical spherical viral particle with high specificity. The viral genome consists of a long control region (LCR), an early region, and a late region.

The LCR region accounts for about 10% of HPV genes and regulates early and late protein translation. The early region accounts for about 50% of HPV genes and mainly carries six open reading frames (ORFs) including E1, E2, E4, E5, E6, and E7. The late region accounts for about 40% of the HPV genome and has two ORFs responsible for encoding the virus's primary capsid protein L1 and secondary capsid protein L2.

Fig.1 Structure map of the HPV genome. (Molina Mariano A., et al., 2024)

Types of HPV infection

At present, there are more than 200 HPV viruses isolated from humans, and the identification of HPV types is mainly based on a 291 bp fragment located on the L1 ORF gene. It is usually divided into high-risk and low-risk types, and can be further divided into four types according to the different tissue sites of invasion.

Low-risk skin type: It involves common warts, flat warts, plantar warts, etc., including human papillomavirus types 1, 2, 3, 4, 7, 10, 12, 15, etc.

High-risk skin type: It may also include vulvar, penile, anal, prostate, bladder and other cancers, including HPV types 5, 8, 14, 17, 20, 36, 38.

Low-risk mucosal type: It may also include vulvar, penile, anal, prostate, bladder and other cancers, including HPV types 5, 8, 14, 17, 20, 36, 38.

High-risk mucosal type: It mainly causes cervical cancer, rectal cancer, oral cancer, tonsil cancer, etc., including human papillomavirus types 16, 18, 30, 31, 33, 35, and 39.

Human papillomavirus test

There are many ways to detect HPV, and the sensitivity and specificity of each test are different.

Second-generation hybridization capture (HC2) detection method: Its essence is molecular hybridization signal amplification technology. The assay uses a polygenic RNA probe that can detect 13 high-risk HPV types.

HPV-HR detection method: In the isothermal reaction environment, the molecular structure of the target DNA was specifically identified and cleaved by the cleavage enzyme, and the identification and detection of 14 high-risk HPV-DNA types were completed by using specific probes that can detect L1, E6 and E7 gene sequences.

Real-time PCR (Cobas 4800) detection: This assay uses multiplex real-time PCR and nucleic acid hybridization with 4 fluorescent reporter probes to simultaneously detect the nucleotide sequences of L1 genes of 14 high-risk HPV types.

Reverse transcription amplification (Aptima HPV) assay: This method indirectly determines HPV-DNA content by detecting mRNA of high-risk HPV E6/E7 oncogenes.

HPV-related diseases

The HPV virus is highly epithelial and selectively infects only skin and mucosal epithelial cells. Breakdown of the skin or mucous membranes is a triggering condition for HPV infection. The clinical manifestations are varied, ranging from asymptomatic to benign warts, to neoplasia or even invasive cancer. Depending on the site of the tissue that is violated, it can cause the following major diseases:

Cervical intraepithelial neoplasia (CIN) or cervical cancer: Strongly associated with multiple types of HPV infection. Studies have shown that more than 90% of CIN and 99.7% of cervical cancer patients are caused by HPV infection. Among them, HPV16 and 18 were the main causes of cervical cancer, which were associated with 69.4% of invasive cancers.

Cutaneous papilloma: There are mainly plantar warts, common warts (the most common), flat warts. Epidermoplasia Verrucosum (EV) is uncommon, and about one-third of EV patients progress to Bowen's disease or squamous cell carcinoma. HPV5 and hpv8 are detected in about 90% of squamous cell carcinomas.

Respiratory papilloma: It is a benign tumor, mostly caused by HPV6 and 11, which can occur in children and adults, and grows in the larynx.

Other diseases: 1/3 of penile cancers, 65% of vaginal tumors and 95% of anal cancers are caused by the HPV virus. Some head and neck cancers and oropharyngeal cancers (about 20%-60%) are also associated with HPV.

Human papillomavirus infection treatments

Vaccine therapy

The current research on HPV vaccines is mainly aimed at high-risk HPV types, including prophylactic vaccines and therapeutic vaccines, the prophylactic vaccines mainly resist HPV infection by inducing an effective humoral immune response, that is, the production of neutralizing antibodies, while the therapeutic vaccines mainly stimulate the cellular immune response to eliminate virus-infected or mutated cells. According to the number of HPV virus subtypes that can be prevented, it can be divided into bivalent, quadrivalent and 9-valent HPV vaccines.

Medicine therapy

There is currently no effective drug that can completely clear HPV infection. However, there are several commonly used drugs that can be used to treat HPV infection, including local immunomodulators, antiviral drugs, cytotoxic drugs, and targeted drugs.

Topical immunomodulators: Such as Interferon, these drugs can boost the immune system and help the body fight off HPV infection. It is usually indicated for mild to moderate infections and is often used in combination with other treatments.

Antiviral drugs: Such as HPV18-IN-1, Acyclovir, and Teslexivir, can inhibit the replication of the HPV virus, thereby reducing the symptoms of infection. Antiviral drugs are usually used in patients with severe or long-term HPV infection, but it is important to note that although these drugs can suppress viral activity, they cannot completely eliminate the HPV virus from the body.

Cytotoxic drugs: Fluorouracil is a commonly used cytotoxic drug, which can be applied directly to the damaged area of the skin, so as to achieve a good therapeutic effect. In addition, bleomycin has also been used to treat HPV-related lesions and reduce symptoms by killing infected cells.

Targeted drugs: Targeted drugs such as Cetuximab work on human epidermal growth factor receptors to prevent the replication of the HPV virus, thereby achieving therapeutic effects. Targeted drugs have a good effect on patients with HPV infection under certain circumstances.

While no drug has been developed that can effectively inhibit HPV, researchers have analyzed a variety of compounds and targets. For example, E1 and E2 are two viral proteins that are essential for HPV genome replication and are potential drug targets. In addition, the viral genome itself may also become a target. Several sequence-specific DNA-binding compounds belonging to the pyrrole-imidazole polyamide class have been developed that specifically bind to specific DNA sequences and thus interfere with the replication process of the virus.

Reference

• Molina, Mariano A., et al., HPV integration and cervical cancer: a failed evolutionary viral trait. Trends in molecular medicine (2024).

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