Gut Helminth Infection-Induced Immunotolerance and Consequences for Human Papillomavirus Persistence

Eva H. Clark Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, Texas;
Department of Medicine, Section of Health Services Research, Center for Innovations in Quality, Effectiveness, and Safety (IQuESt), Michael E. DeBakey VA Medical Center, Houston, Texas;
National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas;

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Robert H. Gilman Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland;

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Elizabeth Y. Chiao Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas;
Department of General Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas;

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Patti E. Gravitt Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland

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ABSTRACT.

Cervical cancer, a malignancy caused by persistent human papillomavirus (HPV) infection, develops in more than 500,000 women annually. More than 90% of deaths from cervical cancer occur in low- and middle-income countries. A common epidemiological feature of countries with high cervical cancer incidence is a high burden of intestinal helminth infection. The ability of intestinal helminths to trigger immunoregulation, resulting in a “tolerogenic” systemic immune environment, provides fertile soil for the persistence of oncogenic viruses such as HPV. Animal models have shown that intestinal helminth infection permits the persistence of some viruses, however, HPV-specific and human studies are lacking. Large, well-organized trials evaluating the consequences of intestinal helminth infection on the human immune system and HPV persistence may lead to improved strategies for HPV prevention in helminth-endemic regions of the world. Additionally, such studies would offer insight into the specific ways that intestinal helminth infection contributes to immunomodulation, which could identify new therapeutic targets for a range of diseases, from inflammatory disorders to cancer. In this review, we discuss the evidence for helminth-induced systemic and local immune dysregulation, discuss possible mechanisms by which chronic intestinal helminth infection may facilitate HPV persistence, and suggest novel helminth-related interventions that could offer a high leverage (if somewhat unconventional) approach to HPV and cervical cancer control in resource-constrained regions.

Author Notes

Address correspondence to Eva H. Clark, Houston HSR&D Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Baylor College of Medicine, Michael E. DeBakey VA Medical Center, 2450 Holcombe Blvd., Suite 01Y, Houston, TX 77021. E-mail: eva.clark@bcm.edu

Financial support: This work was supported by VA Health Services Research & Development Center of Innovation grant CIN 13-413 (E. H. C. receives salary support in part from the Houston VA HSR&D Center for Innovations in Quality, Effectiveness and Safety [CIN13-413] Advanced Fellowships Program in Health Services Research).

Authors’ addresses: Eva H. Clark, Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, TX, Department of Medicine, Section of Health Services Research, Center for Innovations in Quality, Effectiveness, and Safety (IQuESt), Michael E. DeBakey VA Medical Center, Houston, TX, and National School of Tropical Medicine, Baylor College of Medicine, Houston, TX, E-mail: eva.clark@bcm.edu. Robert H. Gilman, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, E-mail: gilmanbob@gmail.com. Elizabeth Y. Chiao, Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, and Department of General Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, E-mail: eychiao@mdanderson.org. Patti E. Gravitt, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, E-mail: pgravitt@som.umaryland.edu.

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