Charlene Dezzutti from the University of Pittsburgh and the Magee-Womens Research Institute explains how HIV researchers are incorporating biomarkers and preclinical testing – featured in the PLOS Collection Advances in HIV Mucosal Immunology: Challenges and Opportunities – in their pursuit of an effective HIV preventative such as a topical microbicide gel or an oral pill containing anti-retroviral drugs or a vaccine.
Biomarkers are biological substances that mark the presence of a disease or condition in a person. For instance, cholesterol level is a biomarker for heart disease and CD4+ T cell counts or plasma HIV RNA levels are biomarkers for HIV disease progression. Biomarkers are important because they allow physicians to track an individual patient’s condition during treatment to better predict and improve health outcomes.
Likewise, biomarkers of product safety and efficacy would provide a tremendous benefit to the HIV prevention field because they would help identify preventatives that are safe and effective. Since newly developed experimental products cannot be tested in humans, models that accurately predict how humans would react – called “preclinical models” – are used. Because HIV in adults is usually transmitted sexually, with the exception of intravenous drug users, researchers have been targeting the tissues and routes that first encounter the virus to better understand the dynamic host-pathogen interaction. Researchers are now working to develop and test animal and ex vivo tissue culture models to try and predict how these new HIV prevention products will work in people. The latest models use human mucosal tissue and secretions as well as non-human primates to mimic as closely as possible human exposures and potential responses.
Once a product has success in these models, it then moves into small phase 1 human clinical trials to evaluate drug dissemination and host responses. These initial trials are typically completed in the country where the product was developed and focus on safety. However, differences between persons across the globe, and between genders, are becoming increasingly clear. To begin addressing these differences, these trials will need to be done in varied geographic locations, in different ethnic backgrounds, and in both men and women. To help identify the same or similar biomarkers in humans as in these preclinical models, the feasibility of taking many mucosal samples and the best sampling practices are key issues to address that will allow researchers the opportunity to identify HIV exposure, measure immune responses, and better define product efficacy and potential side effects.
To help in these efforts, the U.S. National Institute of Allergy and Infectious Diseases and the Bill & Melinda Gates Foundation have supported the HIV Mucosal Immunology Group (MIG) in bringing together expert scientists who are coordinating their efforts to standardize and improve mucosal sample procurement, collection and storage methodologies, define biomarkers of HIV exposure, assess rectal or genital innate immunity, and harmonize HIV product testing to advance new HIV prevention concepts. In the PLOS Collection Advances in Mucosal Immunology: Challenges and Opportunities, MIG investigators report the results of their efforts, providing important baseline data in the genital and rectal mucosa, which will help guide future studies of HIV prevention with vaccines, topical microbicides and oral pre-exposure prophylaxis.
About the Author: Charlene Dezzutti obtained her PhD at The Ohio State University studying viral immunology and worked at the US Centers for Disease Control and Prevention for over 12 years before joining the University of Pittsburgh as an Associate Professor in the Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine. She currently is the Principal Investigator for the Microbicide Trials Network’s Laboratory Center where she oversees laboratory testing and assay development for several clinical trials. Her laboratory focuses on evaluating the safety and efficacy of topical and injectable products designed for HIV/STI prevention using ex vivo tissue models like those described above.