Unmasking Human Papillomavirus (HPV)

Within the realm of infectious diseases, a subtle intruder has stealthily made its way into the human population, silently affecting millions worldwide. This covert assailant is none other than the human papillomavirus (HPV). Although HPV frequently remains asymptomatic, recent years have witnessed growing concerns about its infections due to its potential to lead to cancer, notably cervical cancer. In this article, HPV origins, transmission by physical contact, associated diseases, such as cancer, and prevention strategies, such as vaccines, will be explored, providing a comprehensive overview of the topic.

Origins, Traits, and Transmission of HPV

HPV is not a recent invader of the human body—it has likely coexisted with our species for millennia (Chen et al., 2011). It belongs to the Papillomaviridae family, whose origins can be traced back to the time when mammals first appeared on Earth. Over millions of years, these viruses have evolved alongside their hosts, adapting to exploit the cellular machinery of their respective hosts to replicate and propagate. Papilomaviridae is a family of small, non-enveloped viruses characterized by their unique structural composition. These viruses consist of proteins that self-assemble into distinctive star-shaped shields. Remarkably, a total of seventy-two of these starry shields come together to form the capsid, a protective structure that encases the viral DNA (Santos-López et al., 2015) [Figure 1].

Over 200 different types of HPV have been identified and they are designated by numbers (Bzhalava et al., 2013). They can be divided into low-risk and high-risk types. While low-risk types are associated with issues that are not a big health threat, like warts, high-risk ones are associated with more serious health conditions like cancer (Schiffman & Castle, 2003). Among all of them, approximately 50 types can infect the genital and oral regions. Fifteen of them are classified as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82), three as probable high-risk (26, 53, and 66), and twelve as low-risk (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and 89) (Muñoz et al., 2003) [Figure 1]. One unique aspect of HPV is its ability to persist in the human body for extended periods of time. After initial infection, the virus can remain dormant or latent in the body for years or even decades. During this time, an infected individual can still transmit the virus to other people, even if they are asymptomatic.

Figure 1: The structure and types of HPV (Neunez, 2021).

HPV is primarily transmitted by direct skin-to-skin contact. This transmission occurs when an individual's skin, mucous membranes (moist linings of various body cavities), or genital secretions come into contact with an infected person's skin or mucous membranes. HPV can infect the genital and anal areas, as well as the mouth and throat, making it highly transmissible through sexual activities (Pahud & Ault, 2015). This includes vaginal, anal, and oral sex. While sexual contact is the primary mode of transmission, HPV can also spread through non-sexual contact (Pao et al., 1993). This includes close personal contact such as kissing or touching the genital or anal areas of an infected person. HPV can also be transmitted from an infected mother to her newborn during childbirth, which can result in respiratory papillomatosis, a rare condition in which warts develop in the airway of the child (Sinal & Woods, 2005).

HPV Associated Diseases

HPV infections are often asymptomatic, but sometimes they exhibit symptoms or lead to the development of different diseases. Infection with some low-risk HPV types can lead to benign conditions, such as warts or condylomas. On the other hand, infections by high-risk HPV types are more dangerous and can cause malignant lesions, such as cancer (Muñoz et al., 2003) [Figure 2].

Figure 2: Lesions associated with HPV infection (Neunez, 2021).

Skin infections with HPV can give rise to noncancerous skin growths known as warts. These warts result from the rapid multiplication of cells on the outer layer of the skin and can be classified depending on their anatomy or location (Antonsson et al., 2000) [Figure 3]. Common warts are typically located on the hands and feet but can also appear in other areas like the elbows or knees. They are characterized by their distinctive cauliflower-like texture and are usually slightly raised above the surrounding skin. Some cutaneous HPV types can cause genital warts, but they are not linked to the development of cancer. Plantar warts, on the other hand, are found on the soles of the feet and grow inward, often causing discomfort when walking. Fingernail warts can be more challenging to treat than warts in other locations. They can be subclassified into subungual if they are around the fingernail or periungual if they are on the cuticle. Flat warts are most commonly found on the arms, face, or forehead, with a higher incidence among children and teenagers. Finally, filiform warts can develop on the face, especially around the eyes and the lips. They are characterised by long, narrow projections that extend a few millimetres from the skin.

It is worth noting that the types of HPV responsible for genital warts are typically distinct from those causing warts on other body parts. Various HPV types can lead to genital warts, with types 6 and 11 being responsible for approximately 90% of all cases (Greer et al., 1995). Furthermore, HPV types 6 and 11 infections can result in a rare condition called recurrent laryngeal papillomatosis, characterized by the formation of warts in the larynx or other parts of the respiratory tract (Sinal & Woods, 2005). These warts may recur frequently, potentially presenting a problem with normal breathing. In exceedingly rare instances, these warts can progress to cancer. Due to these concerns, surgical interventions to remove the warts may be advisable (Moore et al., 1999).

Figure 3: Types of warts (Dermatology Physicians Group, n. d.).

The most widely known implication of HPV in cancer development is the case of cervical cancer [Figure 4]. In its early stages, cervical cancer often lurks without apparent symptoms. However, as the disease advances, signs may surface, including abnormal vaginal bleeding, pelvic discomfort, or discomfort during sexual intercourse. Notably, post-sexual activity bleeding can raise suspicion of cervical cancer. On a global scale, cervical cancer ranks as the fourth most common cancer among individuals with a cervix and stands as the fourth leading cause of cancer-related deaths in this population. Remarkably, HPV infection is implicated in 90% of cervical cancer cases. Among these cancer cases, HPV types 16 and 18 are detected in roughly 70% of instances (Baseman & Koutsky, 2005).

Moving beyond cervical cancer, HPV's influence extends to various other malignancies, including anal, vulvar, vaginal, penile, and oropharyngeal cancers. Notably, sexually transmitted HPVs are prevalent in a significant proportion of anal cancers (Parkin, 2006). Moreover, the risk of anal cancer skyrockets from 17 to 31 times higher in individuals coinfected with high-risk HPV and the human immunodeficiency virus (HIV). For HIV-positive homosexual men, this risk surges to a staggering 80 times higher. Additionally, HPV is associated with approximately 50% of penile cancers, and the risk of penile cancer escalates 2- to 3-fold in individuals infected with both HIV and HPV (Burd & Dean, 2016). Furthermore, oral infection with high-risk carcinogenic HPV types, most commonly HPV 16, is increasingly linked to a rising number of head and neck cancers (Ault, 2006), marking another facet of HPV's extensive impact on health.

Figure 4: Cancerous tissues forming in the cervix (Cleveland Clinic, 2021).

HPV Cancer Induction

HPV's pivotal role in cancer development lies in its ability to integrate genetic material into the host cell's nuclear DNA. This integration process can serve as a catalyst for carcinogenesis by promoting genomic instability, resulting in changes in DNA copy numbers (McBride, 2017). Furthermore, high-risk HPV types produce two viral oncogenic proteins known as E6 and E7, and these proteins play a critical role in cancer development by inactivating two tumour suppressor proteins, namely p53 (disabled by E6) and pRb (targeted by E7) (Münger & Howley, 2002). E6 forms a complex with a host protein called E6-associated protein, which possesses ubiquitin ligase activity. This complex leads to the ubiquitination of p53, resulting in its degradation within the proteasome and consequent inactivation of its tumour suppressor function. Conversely, E7 functions as the primary transforming protein, as it can bind to the retinoblastoma protein (pRb) and inhibit its function. Normally pRb inhibits the transcription factor E2F in order to control the cell cycle. The inhibition of pRb by the E7 protein causes the activation of E2F, promoting the cell cycle forward. Based on that, new therapies are trying to target E6 and E7 viral oncogene proteins (Paolini et al., 2021) [Figure 5].

Figure 5: Mechanisms of action of therapeutics that target E6 and E7 proteins (Paolini, 2021).

Prevention of HPV Infection

There is no cure for HPV infection. The sole recourse is to proactively prevent HPV infection from occurring in the first place. The development of HPV vaccines represents a significant breakthrough in the battle against this virus. At present, there are many vaccines developed to prevent infection by specific HPV types, but the three most common ones are Gardasil, Gardasil 9 [Figure 6], and Cervarix (Kamolratanakul & Pitisuttithum, 2021). All three vaccines provide protection against the initial infection by HPV types 16 and 18, which are responsible for the majority of HPV-associated cancer cases. Additionally, Gardasil and Cervarix offer protection against HPV types 6 and 11. Gardasil 9 protects the four previously mentioned and from five other high-risk HPV types responsible for 20% of cervical cancer, namely types 31, 33, 45, 52, and 58 (Zhai & Tumban, 2016). The vaccines offer limited advantages to individuals with a cervix who are already infected with HPV types 16 and 18. Therefore, vaccination is primarily recommended for individuals with a cervix who have not yet been exposed to HPV through sexual activity (Koliopoulos et al., 2017).

The HPV vaccine is composed of reconstructed viral structures known as "virus-like particles" or VLPs. These VLPs closely resemble the HPV virus in appearance but are entirely harmless to humans as they do not contain any viral genetic material. They are artificially produced in laboratories using yeast cells to mimic the virus's structure. When an individual receives the HPV vaccine, their immune system responds to these VLPs and builds a memory of them. If the person is exposed to HPV in the future, their immune system will recognize the starry shield-like structure of the virus and mount a rapid defence to eliminate the virus from their body.

Figure 6. Garadasil-9 vaccine (Unanderra Family Doctors, n. d.).

Apart from the vaccines, another way to prevent HPV transmission is to consistently use latex or polyurethane condoms during sexual activity. However, condoms do not provide complete protection as they do with other sexually transmitted viruses. This is because HPV may also be transmitted by exposure to areas (e.g., infected skin or mucosal surfaces) that are not covered or protected by the condom.

Regular screening for HPV is also a critical component of preventive healthcare, especially for individuals with cervix (Fuzzell et al., 2021). Early detection of HPV infection and intervention can help prevent the development of cervical cancer. There are two primary methods for HPV screening, the Pap smear, which consists of collecting cells from the cervix and examining them under a microscope to detect abnormal changes in cervical cells (Nkwabong et al., 2019), and the DNA test, which directly checks for the presence of high-risk HPV strains in cervical cells. The DNA test is normally used as a follow-up when abnormal results are found on a Pap smear. If an HPV infection is detected through screening, especially if it is a high-risk strain, additional testing, close monitoring, or interventions can be performed to prevent the progression of cervical abnormalities. The frequency of HPV screening depends on various factors, including age, previous screening results, and individual risk factors. In some cases, screening may be recommended every three years, while in others, it may be more or less frequent.

Conclusion

HPV is a silent but pervasive threat that affects millions of individuals worldwide. Its association with various cancers and non-cancerous conditions highlights the importance of understanding and preventing HPV infections. Through vaccination, safe sexual practices, regular screening, and increased awareness, we can reduce the impact of HPV on global health. Ongoing research and innovations offer hope for better treatments and more effective prevention strategies, bringing us closer to a world where HPV-related diseases are rare occurrences rather than common threats. All of us, as well as healthcare providers, and policymakers must work together to combat this hidden adversary and protect the health and well-being of future generations.

Bibliographical References

Antonsson, A., Forslund, O., Ekberg, H., Sterner, G., & Hansson, B.G. (2000). The ubiquity and impressive genomic diversity of human skin papillomaviruses suggest a commensalic nature of these viruses. Journal of Virology 74(24), 11636–11641. https://doi.org/10.1128/jvi.74.24.11636-11641.2000

Ault, K.A. (2006). Epidemiology and natural history of human papillomavirus infections in the female genital tract. Infectious Diseases in Obstetrics and Gynecology 2006 Suppl, 40470. https://doi.org/10.1155/idog/2006/40470 Baseman, J.G., & Koutsky, L.A. (2005). The epidemiology of human papillomavirus infections. Journal of Clinical Virology: the Official Publication of the Pan American Society for Clinical Virology 32 Suppl 1, S16-24. https://doi.org/10.1016/j.jcv.2004.12.008 Burd, E.M., & Dean, C.L. (2016). Human papillomavirus. Microbiology Spectrum 4(4). https://doi.org/10.1128/microbiolspec.dmih2-0001-2015 Bzhalava, D., Guan, P., Franceschi, S., Dillner, J., & Clifford, G. (2013). A systematic review of the prevalence of mucosal and cutaneous human papillomavirus types. Virology 445(1-2), 224–231. https://doi.org/10.1016/j.virol.2013.07.015 Chen, Z., Schiffman, M., Herrero, R., Desalle, R., Anastos, K., Segondy, M., Sahasrabuddhe, V. V, Gravitt, P.E., Hsing, A.W., & Burk, R.D. (2011). Evolution and taxonomic classification of human papillomavirus 16 (HPV16)-related variant genomes: HPV31, HPV33, HPV35, HPV52, HPV58 and HPV67. PLoS One 6(5), e20183. https://doi.org/10.1371/journal.pone.0020183

Fuzzell, L.N., Perkins, R.B., Christy, S.M., Lake, P.W., & Vadaparampil, S.T. (2021). Cervical cancer screening in the United States: Challenges and potential solutions for underscreened groups. Preventive Medicine 144, 106400. https://doi.org/10.1016/j.ypmed.2020.106400

Greer, C.E., Wheeler, C.M., Ladner, M.B., Beutner, K., Coyne, M.Y., Liang, H., Langenberg, A., Yen, T.S., & Ralston, R. (1995). Human papillomavirus (HPV) type distribution and serological response to HPV type 6 virus-like particles in patients with genital warts. Journal of Clinical Microbiology 33(8), 2058–2063. https://doi.org/10.1128/jcm.33.8.2058-2063.1995

Kamolratanakul, S., & Pitisuttithum, P. (2021). Human papillomavirus vaccine efficacy and effectiveness against cancer. Vaccines 9(12),1413. https://doi.org/10.3390/vaccines9121413 Koliopoulos, G., Nyaga, V.N., Santesso, N., Bryant, A., Martin-Hirsch, P.P., Mustafa, R.A., Schünemann, H., Paraskevaidis, E., & Arbyn, M. (2017). Cytology versus HPV testing for cervical cancer screening in the general population. The Cochrane Database of Systematic Reviews 8(8), CD008587. https://doi.org/10.1002/14651858.cd008587.pub2 McBride, A.A. (2017). Mechanisms and strategies of papillomavirus replication. Biological Chemistry 398(8), 919–927. https://doi.org/10.1515/hsz-2017-0113 Moore, C.E., Wiatrak, B.J., McClatchey, K.D., Koopmann, C.F., Thomas, G.R., Bradford, C.R., & Carey, T.E. (1999). High-risk human papillomavirus types and squamous cell carcinoma in patients with respiratory papillomas. Otolaryngology-Head and Neck Surgery: Official Journal of American Academy of Otolaryngology-Head and Neck Surgery 120(5), 698–705. https://doi.org/10.1053/hn.1999.v120.a91773 Münger, K., & Howley, P.M. (2002). Human papillomavirus immortalization and transformation functions. Virus Research 89(2), 213–228. https://doi.org/10.1016/s0168-1702(02)00190-9 Muñoz, N., Bosch, F.X., de Sanjosé, S., Herrero, R., Castellsagué, X., Shah, K. V, Snijders, P.J.F., & Meijer, C.J.L.M. (2003). Epidemiologic classification of human papillomavirus types associated with cervical cancer. The New England Journal of Medicine 348(6), 518–527. https://doi.org/10.1056/nejmoa021641

Nkwabong, E., Laure Bessi Badjan, I., & Sando, Z. (2019). Pap smear accuracy for the diagnosis of cervical precancerous lesions. Tropical Doctor 49(1), 34–39. https://doi.org/10.1177/0049475518798532

Pahud, B.A., & Ault, K.A. (2015). The expanded impact of human papillomavirus vaccine. Infectious Disease Clinics of North America 29(4), 715–724. https://doi.org/10.1016/j.idc.2015.07.007 Pao, C.C., Tsai, P.L., Chang, Y.L., Hsieh, T.T., & Jin, J.Y. (1993). Possible non-sexual transmission of genital human papillomavirus infections in young women. European Journal of Clinical Microbiology & Infectious Diseases: Official Publication of the European Society of Clinical Microbiology 12(3), 221–222. https://doi.org/10.1007/bf01967118 Paolini, F., Amici, C., Carosi, M., Bonomo, C., Di Bonito, P., Venuti, A., & Accardi, L. (2021). Intrabodies targeting human papillomavirus 16 E6 and E7 oncoproteins for therapy of established HPV-associated tumors. Journal of Experimental & Clinical Cancer Research. 40(1), 37. https://doi.org/10.1186/s13046-021-01841-w Parkin, D.M. (2006). The global health burden of infection-associated cancers in the year 2002. International Journal of Cancer 118(12), 3030–3044. https://doi.org/10.1002/ijc.21731 Santos-López, G., Márquez-Domínguez, L., Reyes-Leyva, J., & Vallejo-Ruiz, V. (2015). General aspects of structure, classification and replication of human papillomavirus. Revista Medica del Instituto Mexicano del Seguro Social 53 Suppl 2, S166-71. http://revistamedica.imss.gob.mx/editorial/index.php/revista_medica/article/view/184/541 Schiffman, M., & Castle, P.E. (2003). Human papillomavirus: Epidemiology and public health. Archives of Pathology & Laboratory Medicine 127(8), 930–934. https://doi.org/10.5858/2003-127-930-hpeaph Schiller, J.T., Day, P.M., & Kines, R.C. (2010). Current understanding of the mechanism of HPV infection. Gynecologic Oncology 118(1), S12-7. https://doi.org/10.1016/j.ygyno.2010.04.004 Sinal, S.H., & Woods, C.R. (2005). Human papillomavirus infections of the genital and respiratory tracts in young children. Seminars in Pediatric Infectious Diseases16(4), 306–316. https://doi.org/10.1053/j.spid.2005.06.010 Zhai, L., & Tumban, E. (2016). Gardasil-9: A global survey of projected efficacy. Antiviral Research 130, 101–109. https://doi.org/10.1016/j.antiviral.2016.03.016

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