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

Abstract

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.

Abbreviations

AIDS:

acquired immunodeficiency syndrome

CIN1, CIN2, and CIN3:

light, moderate, and severe cervical intraepithelial neoplasia, respectively

HAART:

highly active antiretroviral therapy

(HR) HPV:

(high carcinogenic risk) human papillomavirus

HSIL and LSIL:

high- and low-grade squamous intraepithelial lesion, respectively

L1 and L2:

large and small capsid proteins of HPV, respectively

LCR, NCR, and URR:

long control region, noncoding region, and upstream regulatory region of HPV genome, respectively

ORF:

open reading frame

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Correspondence to M. Isaguliants.

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Russian Text © The Author(s), 2019, published in Biokhimiya, 2019, Vol. 84, No. 7, pp. 995–1015.

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Vonsky, M., Shabaeva, M., Runov, A. et al. Carcinogenesis Associated with Human Papillomavirus Infection. Mechanisms and Potential for Immunotherapy. Biochemistry Moscow 84, 782–799 (2019). https://doi.org/10.1134/S0006297919070095

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Keywords

  • human papillomavirus (HPV)
  • squamous cell carcinoma
  • carcinogenesis
  • cervical cancer
  • intraepithelial neoplasias
  • epidemiology
  • E6 and E7 oncoproteins