Muscle-type Creatine Kinase as a Regulator of Tenofovir Disposition
One of the newer approaches to decreasing the spread of HIV is pre-exposure prophylaxis (PrEP), wherein people can take a pill daily and decrease the chance they become infected with HIV. Tenofovir (TFV), a key component of FDA-approved PrEP regimens, is dosed as an inactive prodrug that must undergo multiple chemical reactions inside the body before it is active and effective. In colon tissue, a key site related to HIV infection, the last of these activating reactions is performed by muscle-type creatine kinase (CKM), producing the active TFV-diphosphate (TFV-DP) metabolite. While TFV-based PrEP has been shown in clinical trial and real-world settings to reduce the chance of HIV infection, it has not been 100% effective; and lack of efficacy results in lifelong infection. The goal of this research project is to study how person-to-person variation in the ability of one’s body to activate TFV may contribute to these variable outcomes. Thus, assessment of the impact of genetics and age on CKM and its role in TFV activation and distribution is being performed. The effects of naturally-occurring mutations to CKM on its structure, endogenous activities, and ability to form TFV-DP in vitro are being evaluated. Mouse models will enable comparisons of how TFV-DP and CKM levels may change as a function of age. The impact of age on TFV-DP and CKM distributions in colon tissue will be studied using mass spectrometry imaging. These studies will inform us about the role of CKM in the inter-individual variability in PrEP outcomes and potentially create a path toward more personalized PrEP prescribing.
Receiving a PhRMA Foundation Predoctoral Fellowship in Pharmacology/Toxicology is an honor and it supports my research as a graduate student. I am lucky to have the chance to partake in research that could improve the health and well-being of many people. This fellowship helps fuel my desire to continue such research and advance toward my future career.