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REVIEW: Carcinogenesis Associated with Human Papillomavirus Infection. Mechanisms and Potential for Immunotherapy

M. Vonsky1,2,a, M. Shabaeva3,b, A. Runov1,2,4, N. Lebedeva4,5,c, S. Chowdhury6, J. M. Palefsky6,d, and M. Isaguliants4,7,8,9,e*

1Institute of Cytology, Russian Academy of Sciences, 194064 St. Petersburg, Russia

2Almazov National Medical Research Center, 197341 St. Petersburg, Russia

3Pavlov First St. Petersburg State Medical University, 197022 St. Petersburg, Russia

4Gamaleya Federal Research Center for Epidemiology and Microbiology, 123098 Moscow, Russia

5Moscow Regional Center of AIDS and Infectious Diseases Prevention and Treatment, 129110 Moscow, Russia

6University of California, San Francisco School of Medicine, CA 94143 San Francisco, USA

7Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products, Russian Academy of Sciences, 108819 Moscow, Russia

8Karolinska Institutet, Department of Microbiology, Tumor and Cell Biology, SE-171 77 Stockholm, Sweden

9Riga Stradins University, Department of Pathology, LV-1007 Riga, Latvia

* To whom correspondence should be addressed.

Received April 2, 2019; Revised April 19, 2019; Accepted April 21, 2019
Human papillomavirus (HPV) infection is responsible for approximately 5% of all cancers and is associated with 30% of all pathogen-related cancers. Cervical cancer is the third most common cancer in women worldwide; about 70% of cervical cancer cases are caused by the high-risk HPVs (HR HPVs) of genotypes 16 and 18. HPV infection occurs mainly through sexual contact; however, viral transmission via horizontal and vertical pathways is also possible. After HPV infection of basal keratinocytes or ecto-endocervical transition zone cells, viral DNA persists in the episomal form. In most cases, infected cells are eliminated by the immune system. Occasionally, elimination fails, and HPV infection becomes chronic. Replication of HPVs in dividing epithelial cells is accompanied by increased expression of the E6 and E7 oncoproteins. These oncoproteins are responsible for genomic instability, disruption of the cell cycle, cell proliferation, immortalization, and malignant transformation of HPV-infected cells. Besides, E6 and E7 oncoproteins induce immunosuppression, preventing the detection of HPV-infected and transformed cells by the immune system. HPV integration into the genome of the host cell leads to the upregulation of E6 and E7 expression and contributes to HPV-associated malignization. Prophylactic HPV vaccines can prevent over 80% of HPV-associated anogenital cancers. The vaccine elicits immune response that prevents initial infection with a given HPV type but does not eliminate persistent virus once infection has occurred and does not prevent development of the HPV-associated neoplasias, which necessitates the development of therapeutic vaccines to treat chronic HPV infections and HPV-associated malignancies.
KEY WORDS: human papillomavirus (HPV), squamous cell carcinoma, carcinogenesis, cervical cancer, intraepithelial neoplasias, epidemiology, E6 and E7 oncoproteins

DOI: 10.1134/S0006297919070095