J-107 Interrogating the immunologic and microbial cervical microenvironment in HPV infection
Authors: Gravitt Patti 
Published: April 2019

Infection with high-risk human papillomavirus (hrHPV) infection in the oral and anogenital mucosa has been confirmed to be a necessary but insufficient cause of invasive cervical cancer (ICC), which is a leading cause of cancer incidence and mortality worldwide. Over the past 2 decades, our understanding of the natural history of cervical hrHPV infection has evolved, especially with regard to the influence of co-infections and the dynamics of the cervical microenvironment. For example, it is now recognized that at least a proportion of hrHPV infections are immunologically controlled for long periods of time in an undetectable (latent) state, at risk of recurrent detection (reactivation) upon immune suppression.1 This phenomenon is most clearly illustrated when comparing the HPV natural history in HIV-infected and HIV-uninfected individuals, where both incident and persistent detection of HPV is proportionally increased with increasing immune suppression.2 Multiple new type cervical HPV detection increases nearly 4-fold within weeks of acute HIV infection, suggesting a key role for tissue resident T-cell memory in control of latent HPV infection.3

In HIV-uninfected women, we have observed polarization toward T-helper type 2 immune profiles of the lower genital tract immune microenvironment. In an older, well-screened US population, HPV positive women exhibited immune profiles similar to those described in allergic inflammation.4 In the developing world, we have reported an increased prevalence of HPV infection at older ages in Amazonian women with soil-transmitted helminth (STH) infection, who showed evidence of Th2-skewed immunity in lower genital tract secretions compared with STH-uninfected women.5

This epidemiologic evidence, combined with experimental animal models of papillomavirus infection, collectively implicate a key role of host immunity in the control of cervical HPV infection and, by extension, risk of cervical cancer. This presentation will make a case that the time has come to move human HPV natural history studies away from traditional designs with large sample sizes and long interval censored sampling (eg, every 6 months) to designs with smaller sample sizes and more frequent sampling density (eg, every week) to allow interrogation of the dynamic interplay between the shifting microenvironment and HPV detection. Prioritizing a focus on understanding the dynamics and immune mediators involved in healthy control of HPV infection may be an overlooked fundamental system component required to fully understand the causes of dysregulation of HPV infection and persistent detection. This represents a paradigm shift in studying the molecular epidemiology of human viral infections, reflects more fully a systems approach to understanding biological complexity, and may lead to development of less invasive interventions at earlier stages in viral natural history to prevent severe pathological outcomes.

REFERENCES

1. Gravitt PE. The known unknowns of HPV natural history. J Clin Invest. 2011;121:4593–4599.

2. Strickler HD, Burk RD, Fazzari M, et al. Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women. J Natl Cancer Inst. 2005;97:577–586.

3. Nowak RG, Gravitt PE, Morrison CS, et al. Increases in human papillomavirus detection during early HIV infection among women in Zimbabwe. J Infect Dis. 2011;203:1182–1191.

4. Marks MA, Viscidi RP, Chang K, et al. Differences in the concentration and correlation of cervical immune markers among HPV positive and negative perimenopausal women. Cytokine. 2011;56:798–803.

5. Gravitt PE, Marks M, Kosek M, et al. Soil-transmitted helminth infections are associated with an increase in human papillomavirus prevalence and a T-helper type 2 cytokine signature in cervical fluids. J Infect Dis. 2016;213:723–730.