Human Papillomavirus (HPV)

Human papillomavirus, also called HPV, is a virus capable of causing aberrant tissue growth like warts and has been proved as the sexually transmitted agents which cause invasive cervical cancers and the related precancerous lesions in cervix1. Specific types of HPV may cause cervical cancer in women if the infection lasts for a long time. Other types of cancer, such as vaginal, penile, vulvar, and anal cancers may also be originated from HPV2. Oncogenic and non-oncogenic HPV types cause low-grade scaly intraepithelial lesions (LSIL) of the uterine cervix, while most cervical lesions that are classified as high-grade SIL (HSIL), carcinoma in situ or invasive cancer are positive for oncogenic HPV types. About 70% of invasive cervical cancers are caused by HPV 16 or HPV 18 and about 90% of genital warts are caused by HPV 6 or HPV 111.

Papillomaviruses are small viruses with 55-nm-diameter capsids including double-stranded DNA genomes of approximately 8,000 bp. They are broadly found in the animal kingdom, especially infect epithelial cells, and help the development of wart3. Several studies showed that over 90 % of genital warts are caused by HPV 6 and HPV 113.

Almost 200 types of HPV have been identified so far, and new types are added to this list in time. These viruses can be classified into two categories: mucosal and cutaneous HPVs. Within each of these HPV groups, each virus is designated high or low risk according to the tendency for malignant development of the lesions they cause. Most of the HPVs are low risk and accumulate localized benign warts that do not transform into malignant lesions even if left without treatment. If left untreated, some strains of HPV can cause cellular changes in human body that subsequently lead to cancer. HPV-5 and HPV-8, among the cutaneous HPVs, may be assorted as high risk since they are related to the development of epidermodysplasia verruciformis (EV) which exceedingly rare skin disease that is considered one of the earliest indicators for HPVs to be able to contribute to human tumorigenesis4. HPV-5 and HPV-8-related HPVs have been determined in a high rate of nonmelanoma skin cancers, specifically in patients that develop immune suppression. There have been few molecular studies with EV-type HPVs that facilitate a view regarding the molecular pathways by which these viruses may contribute to skin carcinogenesis. It has been proposed that these viruses might also contribute to skin tumors in immune-competent individuals3.

Figure 1: The structure of HPV. (Adapted from Swiss Institute of Bioinformatics)

Early studies by using VLPs (virus-like particles) emerged that Papillomaviruses bind to many epithelial cells along with other cultured cell lines via an evolutionary conserved proteinaceous receptor abundantly present on the cell surface6. VLPs including L1 capsid protein alone or both L1 and L2 capsid proteins bind in a similar way, meaning that L1 includes the main factor(s) for initial attachment. Most researchers now accept that heparan sulfate proteoglycans (HSPGs) are the critical primary attachment factors, at least for epithelial cells. The support for this conclusion is the inhibition of binding and infection by heparinase treatment or by heparin (a proteinaceous form of heparan sulfate)7.

Figure 2: The human papillomavirus life cycle (where it is taken from?)

Both the papillomavirus E1 and E2 proteins play important roles in viral genome replication. E2 is a DNA-binding transcription factor that interacts with ACCN6GGT motifs in the viral LCR. High-risk HPV E2 proteins have the ability to act as transcriptional activators, but they function as transcriptional repressors of viral gene expression in keratinocytes. In addition to modulating viral gene expression, HPV E2 proteins associate with the viral DNA helicase E1.  This interaction is necessary for efficient origin recognition and viral genome replication.  Papillomavirus E2 proteins also play important roles in viral genome segregation during cell division by tethering viral genomes to mitotic chromosomes.

The investigation of the papillomavirus infection mechanism of the mouse cervicovaginal model has revealed that several similarities exist, however, important differences also exist between infection of epithelial tissue and of cultured cell lines. In both cases, heparan sulfate proteoglycans are the primary attachment factors for papillomaviruses. The infection is slow and asynchronous. The main difference is that the critical heparan sulfate proteoglycans actively found in capsid binding are located on the acellular basement membrane rather than on the cell surface. After, the first set of conformational changes required (is required for) for infection to occur prior to cell surface binding. PVs are the only viruses whereby the infection process is initiated at an extracellular site7. Being aware of this mechanism can lead us to the inhibition of HPV infection by blocking the binding site of the virus or deactivating the virus itself. Several methods and mechanisms were investigated for this purpose and remarkable throughputs have been determined. Antigens via vaccines and lactoferrin, which is a milk protein, are some examples. It has been revealed that this infection could be prevented but it should be remembered that further investigations are required8.

References:

  1. Baseman, Janet G., and Laura A. Koutsky. “The epidemiology of human papillomavirus infections.” Journal of clinical virology32 (2005): 16-24.
  2. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/human-papillomavirus Date of Access: 08.07.2022
  3. Münger, K., Baldwin, A., Edwards, K. M., Hayakawa, H., Nguyen, C. L., Owens, M., & Huh, K. (2004). Mechanisms of human papillomavirus-induced oncogenesis. Journal of virology78(21), 11451-11460.
  4. Jablonska, S., Fabjanska, L., & Formas, I. (1966). On the viral etiology of epidermodysplasia verruciformis. Dermatology132(5), 369-385.
  5. Roden RB, Kirnbauer R, Jenson AB, Lowy DR, Schiller JT. Interaction of papillomaviruses with the cell surface. J Virol 1994;68:7260–6
  6. Schiller, J. T., Day, P. M., & Kines, R. C. (2010). Current understanding of the mechanism of HPV infection. Gynecologic oncology118(1), S12-S17.
  7. Current understanding of the mechanism of HPV infection, Gynecologic Oncology, Volume 118, Issue 1, Supplement 1, 2010, Pages S12-S17, ISSN 0090-8258, https://doi.org/10.1016/j.ygyno.2010.04.004.
  8. Drobni, P., Näslund, J., & Evander, M. (2004). Lactoferrin inhibits human papillomavirus binding and uptake in vitro. Antiviral research64(1), 63-68.

Figure References:

  1. https://www.researchgate.net/figure/The-structure-of-HPV-Adapted-from-Swiss-Institute-of-Bioinformatics-Viral-Zone_fig1_221922588 Date of Access: 09.07.2022
  2. https://constiintaortodoxa.ro/the-human-papillomavirus-life-cycle.php Date of Access :09.07.2022

Inspector: Süleyman ŞAHİN

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  1. Geri bildirim: The Immortal Life of Henrietta Cells - GENÇOMÜ

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