What is the pathophysiology of Human Papillomavirus (HPV) types 16 and 18?

From the Guidelines

Human Papillomavirus (HPV) types 16 and 18 are high-risk oncogenic strains that cause cancer through a well-defined pathophysiological process, infecting basal epithelial cells and integrating their viral DNA into the host cell genome, leading to the expression of key oncogenic proteins E6 and E7, which interfere with critical cellular tumor suppressor pathways. These viral types are responsible for approximately 70% of cervical cancers worldwide, with HPV 16 also strongly associated with oropharyngeal, anal, vulvar, vaginal, and penile cancers 1. The key oncogenic proteins E6 and E7 are then expressed, which interfere with critical cellular tumor suppressor pathways, E6 binds to and degrades p53, preventing apoptosis of abnormal cells, while E7 inactivates retinoblastoma protein (pRb), leading to uncontrolled cell proliferation 1.

Pathophysiology of HPV 16 and 18

The pathophysiology of HPV 16 and 18 involves the infection of basal epithelial cells through microabrasions in the skin or mucosa, where they integrate their viral DNA into the host cell genome. This integration leads to the expression of key oncogenic proteins E6 and E7, which interfere with critical cellular tumor suppressor pathways, resulting in genomic instability, accumulation of mutations, and eventual transformation into cancer cells.

• The expression of E6 and E7 proteins leads to the inactivation of p53 and pRb, respectively, resulting in uncontrolled cell proliferation and apoptosis evasion.
• The disruption of normal cell cycle regulation results in genomic instability, accumulation of mutations, and eventual transformation into cancer cells.
• Persistent infection, rather than transient infection, is the critical factor in cancer development, as most HPV infections are cleared by the immune system within 1-2 years without causing cancer 1.

Clinical Implications

The understanding of the pathophysiology of HPV 16 and 18 has important clinical implications, including the development of screening and early intervention strategies.

• The progression from initial infection to cancer typically occurs over many years, allowing for screening and early intervention.
• HPV vaccination has been shown to be effective in preventing new cervical lesions and reducing the risk of recurrence in women with precancerous cervical lesions 1.
• The use of HPV vaccines, such as the quadrivalent and bivalent vaccines, has been recommended for the prevention of HPV-related cancers, particularly in high-risk populations 1.

From the FDA Drug Label

The FDA drug label does not answer the question.

From the Research

Pathophysiology of HPV 16 and 18

The pathophysiology of Human Papillomavirus (HPV) types 16 and 18 involves the infection of epithelial cells and the subsequent replication cycle, which is intimately linked to epithelial differentiation 2. Key aspects of this process include:

• Infection of dividing basal epithelial cells, where the HPV genome enters the nuclei 2
• Triggering of viral gene expression upon basal cell division, leading to a productive infection 2
• Expression of viral oncoproteins E6 and E7, which activate the cell cycle, inhibit apoptosis, and allow accumulation of DNA damage 2, 3
• Integration of HPV DNA into the host cell genome, contributing to malignant transformation 4

Role of E6 and E7 Proteins

The E6 and E7 proteins play a crucial role in the pathogenesis of HPV 16 and 18, as they:

• Target tumor suppressor proteins p53 and Rb, respectively, leading to their inactivation 3, 5
• Stimulate cell proliferation and inhibit apoptosis, contributing to the development of cancer 2, 3
• Are essential for the maintenance of episomes and the stimulation of differentiated cells to reenter the S phase 5

HPV Integration and Cancer Progression

HPV integration into the host cell genome is a key factor in cancer progression, as it:

• Contributes to the development of malignant tumors 4
• Is more frequent in HPV 18-positive cases than in HPV 16-positive cases 4
• Can lead to the persistence of HPV infection and the development of cancer 2, 4

Immune Response and Therapeutic Strategies

The immune response to HPV 16 and 18 infection can be targeted for therapeutic purposes, including:

• Development of DNA vaccines that target E6 and E7 proteins 6
• Use of recombinant vaccinia viruses expressing HPV 16 and 18 E6-E7 fusion proteins as a booster vaccination 6
• Combination of vaccination with PD-1 antibody blockade to enhance immune responses and control tumor growth 6