Bethany Bayer

 Background: Cervical cancer is the 4^th leading cause of cancer in women worldwide.¹ Over 90% of cervical cancers are caused by the human papillomavirus (HPV), which is most commonly spread through sexual activity.¹ Among the high-risk variants, HPV-16 is the most implicated in cervical cancer.¹ Many HPV infections are asymptomatic, meaning that the diagnosis of infection and precancerous lesions is dependent on routine pelvic exams.² Prevention via the HPV Gardasil-9 vaccine remains critical, as there is currently no treatment for HPV infections and cervical cancer other than surgical tissue removal with chemotherapy and radiation.³ HPV infections can progress to cervical cancer if they are not cleared by the host immune system.⁴ Of the 8 HPV early proteins needed for viral replication, historical research has focused on the E6 and E7 oncoproteins.¹ However, recent studies have shown the E1 protein, which is a helicase essential for HPV replication, may also play a role in viral carcinogenesis.¹ Uncovering E1’s role in cervical cancer could lead to the development of drugs and therapeutic vaccines that can treat persistent HPV infections and cervical cancer.

Objective: In this narrative review, we explored the mechanisms by which the HPV-16 E1 protein can lead to viral immune evasion and persistence, ultimately leading to cervical cancer.

Search Methods: An online search was conducted in the PubMed database using the keywords: “HPV,” E1 protein,” and “cervical cancer.” Only articles published between 2017 and 2023 were reviewed.

Results: Original studies show that the E1 protein could have a role in cervical cancer carcinogenesis, as cells harvested from cervical cancer patients showed an increased expression of E1 protein compared to cells harvested from low risk lesions.⁵ Multiple carcinogenic E1 mechanisms were then explored. First E1 overexpression was seen to lead to cell death due to protein accumulation and DNA damage.⁶ It also led to cell survival through dysregulation of apoptotic pathways in human cells transfected with HPV-16 E1 genetic material.⁶ Apoptosis and necrosis can be carcinogenic by sending survival signals to surrounding cells, causing them to proliferate uncontrollably.⁶ Furthermore, E1 was also shown to play a role in the down-regulation of host immune system genes, such as interferons, leading to decreased viral clearance and uncontrolled proliferation.⁷ Lastly, a study illustrated that cervical cancer patients possessing a decreased T cell response specific to the E1 protein have increased viral proliferation and worse outcomes.⁸ The results suggested that an immunotherapy that potentiates a T cell response to the E1 protein can allow the host to clear the virus in both precancerous and cancerous lesions. Researchers developed a therapeutic vaccine in mice that targeted the E1 protein. This treatment prevented tumor growth and reduced tumor mass.⁹

Conclusion: Studies show that the E1 protein plays a role in cervical cancer carcinogenesis; however, its mechanisms of immune evasion and cell proliferation are extremely intricate and warrant further research. Gaining a better understanding of the protein could allow for the development of a therapeutic treatment for HPV and cervical cancer.

Works Cited:

1. Baedyananda F, Sasivimolrattana T, Chaiwongkot A, Varadarajan S, Bhattarakosol P. Role of HPV16 E1 in cervical carcinogenesis. Front Cell Infect Microbiol. 2022;12:955847. Published 2022 Jul 28. doi:10.3389/fcimb.2022.955847
2. Boda D, Docea AO, Calina D, et al. Human papilloma virus: Apprehending the link with carcinogenesis and unveiling new research avenues (Review). Int J Oncol. 2018;52(3):637-655. doi:10.3892/ijo.2018.4256
3. Cohen PA, Jhingran A, Oaknin A, Denny L. Cervical cancer. Lancet. 2019;393(10167):169-182. doi:10.1016/S0140-6736(18)32470-X
4. Hu Z, Ma D. The precision prevention and therapy of HPV-related cervical cancer: new concepts and clinical implications. Cancer Med. 2018;7(10):5217-5236. doi:10.1002/cam4.1501
5. Baedyananda F, Chaiwongkot A, Bhattarakosol P. Elevated HPV16 E1 Expression Is Associated with Cervical Cancer  Intervirology. 2017;60(5):171-180. doi:10.1159/000487048
6. Baedyananda F, Chaiwongkot A, Varadarajan S, Bhattarakosol P. HPV16 E1 dysregulated cellular genes involved in cell proliferation and host DNA damage: A possible role in cervical carcinogenesis. PLoS One. 2021;16(12):e0260841. Published 2021 Dec 30. doi:10.1371/journal.pone.0260841
7. Castro-Muñoz LJ, Manzo-Merino J, Muñoz-Bello JO, et al. The Human Papillomavirus (HPV) E1 protein regulates the expression of cellular genes involved in immune response. Sci Rep. 2019;9(1):13620. Published 2019 Sep 20. doi:10.1038/s41598-019-49886-4
8. Ma M, Feng Y, Fan P, et al. Human papilloma virus E1-specific T cell immune response is associated with the prognosis of cervical cancer patients with squamous cell carcinoma. Infect Agent Cancer. 2018;13:35. Published 2018 Nov 16. doi:10.1186/s13027-018-0206-5
9. Amador-Molina A, Trejo-Moreno C, Romero-Rodríguez D, et al. Vaccination with human papillomavirus-18 E1 protein plus α-galactosyl-ceramide induces CD8+ cytotoxic response and impairs the growth of E1-expressing tumors. Vaccine. 2019;37(9):1219-1228. doi:10.1016/j.vaccine.2018.12.036