The oncogenic mechanisms of HPV

The oncogenic potential of the virus lies primarily in two early viral proteins: E6 and E7. These proteins are constantly produced in infected cells and act as drivers of malignant transformation, interfering with the "guardians of the genome," p53 and pRb, two fundamental proteins in our body that regulate the cell cycle and the genomic stability of the host cell [3].

The E6 protein and p53 degradation

p53 is a crucial tumor suppressor protein that responds to DNA damage by blocking cell proliferation or inducing apoptosis (programmed cell death) to eliminate damaged cells. The viral protein E6 binds to p53 and promotes its degradation through the ubiquitin-proteasome system [1, 3]. In this way, the infected cell loses its main control mechanism and can accumulate mutations without being destroyed.

The E7 protein and pRb inactivation

The other key protein, E7, targets the retinoblastoma protein (pRb), another tumor suppressor that acts as a "brake" on cell proliferation. pRb is encoded by the RB1 gene, the first tumor suppressor gene to have been identified (in 1986) [1, 3]. pRb normally acts as a "brake" by blocking transcription factors of the E2F family. When active, these factors push the cell to replicate its DNA in preparation for division (S phase). By binding to pRb, E7 inactivates it, releasing E2F and causing the cell to divide uncontrollably [1].

The synergy between E6 and E7 leads to a persistent deregulation of the cell cycle, increased proliferation, and genomic instability, all of which are critical factors for cancer development. Malignant progression is often associated with the integration of viral DNA into the host cell's genome, an event that ensures the stable and uncontrolled expression of the E6 and E7 oncoproteins [2].

Clinical implications: from prevention to therapy
A deep understanding of the oncogenic mechanisms of HPV has guided the development of effective clinical strategies, ranging from primary prevention to targeted therapy.

Primary prevention: vaccination
The best means of preventing HPV-related cancers is prophylactic vaccination [4]. The currently available vaccines, such as the nonavalent vaccines, protect against the most dangerous HPV types, which are responsible for most cervical, anal, and other anatomical site cancers [4]. Vaccination is recommended in adolescence, ideally before the start of sexual activity, to maximize its effectiveness [5]. Global studies have shown a significant reduction in precancerous lesions and cancer incidence rates in vaccinated populations [6].

Screening and diagnosis
Cervical cancer screening has been revolutionized by the introduction of the HPV-DNA test [2, 5]. Unlike the Pap test, which detects cellular abnormalities, the HPV-DNA test directly searches for the DNA of high-risk viral types. This higher sensitivity allows for the identification of persistent infections that require more careful monitoring or treatment. The combination of both tests (co-testing) or the use of the HPV-DNA test alone as primary screening has become a clinical standard in many countries.

Artificial Intelligence for precision screening
A further step forward towards even more accurate diagnosis is the application of artificial intelligence (AI) and machine learning models. These systems analyze test data and, thanks to their ability to identify complex patterns, have improved diagnostic accuracy. An approach of this type has made it possible to increase the test's sensitivity up to 96% and extend the period of diagnostic anticipation up to 10.3 years, offering an unprecedented opportunity for early intervention [7, 8, 9].

New therapeutic frontiers
Research is exploring new targeted therapies. Given the importance of the E6 and E7 proteins for the survival of cancer cells, they are considered ideal targets for the development of drugs and immunotherapies. The goal is to stimulate an immune response that recognizes and destroys the cancer cells expressing these viral oncoproteins [3]. These approaches pave the way for more effective and personalized treatments for patients with HPV-related cancers, especially when standard therapies are insufficient.

Machine learning and Artificial Intelligence in HPV infections

A further step forward in diagnosis has been the application of artificial intelligence (AI) and machine learning models. This approach has significantly improved the accuracy of tests.

In the specific case of oropharyngeal cancer risk, the integration of AI has led to extraordinary results, increasing diagnostic sensitivity to 96% and extending the period of diagnostic anticipation to 10.3 years. This technology offers an unprecedented predictive capability, allowing at-risk patients to be identified well in advance.

Conclusion

Although HPV is a common virus, it represents a significant global oncological threat. The understanding of its oncogenic mechanisms has allowed for the development of prevention and diagnostic tools that are already saving lives. The large-scale implementation of vaccination and screening programs is fundamental to drastically reducing the global burden of HPV-related cancers. Scientific research continues to shed light on the mechanisms of its pathogenesis, opening new frontiers for future, even more targeted and personalized therapies.

Bibliography

1. Zhang, Y., et al. "Roles of human papillomavirus in cancers: oncogenic mechanisms and clinical use." Signal Transduction and Targeted Therapy, Nature Publishing Group, 2025.

2. Pan, X., et al. "From Viral Infection to Genome Reshaping: The Triggering Role of HPV Integration in Cervical Cancer." MDPI, 2025.

3. Khaerunnisa, S., et al. "Molecular Insights into HPV-Driven Head and Neck Cancers: From Viral Oncoproteins to Precision Therapeutics." MDPI, 2025.

4. World Health Organization (WHO). "Human papillomavirus and cancer." WHO Fact Sheets, 2024.

5. National Cancer Institute (NCI). "HPV and Cancer." Cancer.gov, 2025.

6. Povey, J., et al. "Evaluating the effectiveness of the human papillomavirus vaccination programme in England, using a regression discontinuity design." Oxford Academic, 2025.

7. Donati G. 13 Set 2025 Oropharyngeal Cancer: vaccine and Artificial Intelligence to predict it years earlier Scienceonline

8. Donati G. 13 Set 2025 Cancro dell'orofaringe: vaccino e intelligenza artificiale per prevederlo anni prima

9. PR TranSpread 14 Gen 2025 Intelligent fight: AI enhances cervical cancer detection Science

More insights

Donati G. 25 Nov 2013 Il Pap Test e la tipizzazione dell'HPV: due test fondamentali Scienzaonline

Donati G. 25 Maggio 2011 Papilloma Virus, HPV, condilomatosi Agenziadistampa

Donati G.30 Giu 2009 Human Papilloma Virus (HPV), cancro del collo dell'utero e vaccino: risultati a due anni dall'esordio Scienzaonline

Donati G.18 Giu 2008 Human Papilloma Virus e altre malattie sessualmente trasmesse (MST) un reale problema di comunicazione Scienzaonline

Donati G.17 Dic 2003 Emergenza Malattie Sessualmente Trasmesse Scienzaonline

**Board Member, SRSN (Roman Society of Natural Science)
Past Editor-in-Chief Italian Journal of Dermosurgery