Genetic variation of the kinases that phosphorylate tenofovir and emtricitabine in peripheral blood mononuclear cells

Citation: Figueroa DB, Madeen EP, Tillotson J, Richardson P, Cottle L, McCauley M, Landovitz RJ, Andrade A, Hendrix CW, Mayer KH, Wilkin T, Gulick RM, Bumpus NN. Genetic variation of the kinases that phosphorylate tenofovir and emtricitabine in peripheral blood mononuclear cells. AIDS Res Hum Retroviruses. 2018 May;34(5):421-429. doi: 10.1089/AID.2017.0243. Epub 2018 Mar 20. PMID: 29455571; PMCID: PMC5934973  

Access full article:

https://www.ncbi.nlm.nih.gov/pubmed/29455571

Tenofovir (TFV) disoproxil fumarate and emtricitabine (FTC) are used in combination for HIV treatment and pre-exposure prophylaxis (PrEP). TFV disoproxil fumarate is a prodrug that undergoes diester hydrolysis to TFV. FTC and TFV are nucleoside/nucleotide reverse transcriptase inhibitors that upon phosphorylation to nucleotide triphosphate analogs competitively inhibit HIV reverse transcriptase. We previously demonstrated that adenylate kinase 2, pyruvate kinase, muscle and pyruvate kinase, liver and red blood cell phosphorylate TFV in peripheral blood mononuclear cells (PBMC). To identify the kinases that phosphorylate FTC in PBMC, siRNAs targeted toward kinases that phosphorylate compounds structurally similar to FTC were delivered to PBMC, followed by incubation with FTC and the application of a matrix-assisted laser desorption ionization-mass spectrometry method and ultra high performance liquid chromatography-UV to detect the formation of FTC phosphates. Knockdown of deoxycytidine kinase decreased the formation of FTC-monophosphate, while siRNA targeted toward thymidine kinase 1 decreased the abundance of FTC-diphosphate. Knockdown of either cytidine monophosphate kinase 1 or phosphoglycerate kinase 1 decreased the abundance of FTC-triphosphate. Next-generation sequencing of genomic DNA isolated from 498 HIV-uninfected participants in the HIV Prevention Trials Network 069/AIDS Clinical Trials Group A5305 clinical study, revealed 17 previously unreported genetic variants of TFV or FTC phosphorylating kinases. Of note, four individuals were identified as simultaneous carriers of variants of both TFV and FTC activating kinases. These results identify the specific kinases that activate FTC in PBMC, while also providing further insight into the potential for genetic variation to impact TFV and FTC activation.

Categories

CRS
Topics

Clinical Trials

P1077FF: Formula Feeding Version of the PROMISE Study...

1077FF is a randomized strategy trial, which is part of the PROMISE studies (1077BF, 1077FF, P1084s, and 1077HS). The Promoting...

Read More

P2010: Phase III Study of the Virologic Efficacy and Safety...

IMPAACT 2010 is a Phase III, three-arm, randomized, open-label study of HIV-1-infected pregnant women initiating either a...

Read More

P2005: A Phase I/II Open-Label, Single-Arm Study to Evaluate...

This study is currently on hold. The study is designed to characterize the pharmacokinetics of DLM using a model-based...

Read More

HPTN083: A Phase 2b/3 Double Blind Safety and Efficacy Study...

HPTN 083 is a study being done to evaluate the efficacy of the long-acting injectable agent, cabotegravir (CAB LA), for...

Read More

A5282: A Randomized, Phase II Trial to Compare an HPV...

The investigators are looking for a better way to prevent cervical cancer. This study is comparing two different methods to...

Read More