Random Stem Cell Divisions May Play Role in Persistent HPV Infections

Marc Ryser PhD Visiting Assistant Professor Department of Mathematics Duke University Durham, North CarolinaMedicalResearch.com Interview with:
Marc Ryser PhD
Visiting Assistant Professor Department of Mathematics
Duke University Durham, North Carolina

Medical Research: What is the background for this study

Dr. Ryser: Infection with the human papillomavirus (HPV) is responsible for approximately 5% of all cancers worldwide. In addition to cervical cancers, HPV is associated with various other female and male cancers, including cancers of the anus and oropharynx. Despite expansive screening and vaccination programs, HPV-related cancers remain a serious public health concern in the US and abroad. To further improve public health interventions against HPV, a thorough understanding of the underlying biology is critical.

The lifetime risk of getting infected with HPV is as high as 80%, yet most individuals remain asymptomatic and clear the virus after 1-2 years.  However, if an infection with a high-risk type of HPV persists, the virus can interfere with the replication mechanism of the host cells, and initiate tumor growth. Even though our understanding is incomplete to date, clearance of HPV infections is primarily attributed to an effective immune response.

Interestingly, recent studies about the stem cell dynamics in epithelial tissues – the types of tissues that are affected by HPV –  have shown that the fate of these stem cells is random: most of the time, a stem cell divides into a new stem cell and a differentiating daughter cell; however, every now and then, a stem cell divides either into two stem cells, or into two differentiating daughter cells. These dynamics have not been acknowledged by the HPV community, and our goal was to develop mathematical models to examine whether the random division patterns of stem cells could play a role in the clearance of HPV infections.

Medical Research: What are the main findings?

Dr. Ryser: We developed a probabilistic model of HPV infection at the tissue level and accounted both for the random division patterns of stem cells and the immune response. Combining the model with data from a longitudinal study of HPV-infected individuals, we found that the random division patterns may contribute quite substantially to the process of clearance. In fact, our results seem to suggest that they may contribute even more to clearance than the immune response.

Medical Research: What should clinicians and patients take away from your report?

Dr. Ryser: Most people clear their HPV infection, while others develop long-lasting infections that can lead to cancer. Our study suggests that chance – in the form of random stem cells divisions – may play an important role in deciding which infections persist, and which ones are cleared. Our model-based predictions need to be confirmed by experimental studies first, but if they are correct, they may help explain controversial epidemiological findings and suggest novel treatment modalities for HPV infections.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Ryser: If our model predictions are correct, there are several possible implications that call for more research.

First, modulation of the stem cell dynamics may provide a fruitful avenue for treatment of HPV infections. For example, increasing the likelihood of symmetric division patterns in these cells would accelerate clearance of the virus.

Second, our results may help explain controversial findings about the association of long-term use of oral contraceptives and cervical cancer risk.

Finally, whether HPV infections can lie dormant for extended periods of time and then re-emerge is debated among experts. Our findings may be able to shed light onto this controversial aspect of the natural history of HPV infections, and hence help improve public health measures against the disease.


HPV Clearance and the Neglected Role of Stochasticity

Marc D. Ryser , Evan R. Myers, Rick Durrett
Published: March 13, 2015
DOI: 10.1371/journal.pcbi.1004113


MedicalResearch.com Interview with: Marc Ryser PhD (2015). Random Stem Cell Divisions May Play Role in Persistent HPV Infections