# Tenofovir inhibition of human mitochondrial polymerase PrimPol and mechanisms of antiviral therapy-driven nephrotoxicity

> **NIH NIH F31** · YALE UNIVERSITY · 2020 · $25,601

## Abstract

Project Summary/Abstract
 Antiviral therapies for the lifelong treatment of HIV has been established to cause nephrotoxic or
cardiotoxic effects. Because there is currently not a cure for HIV, this poses a problem because the toxicity may
affect patient adherence to these drug regimens. It has been observed that nucleoside reverse transcriptase
inhibitors (NRTIs) cause mitochondrial dysfunction, leading to toxicity within the kidneys or heart. A validated
mechanism of toxicity is through the incorporation of NRTIs by DNA polymerase γ, the primary replicative
polymerase within the mitochondria, compromising replication. However, this mechanism is validated only for a
subset of NRTIs, suggesting that other polymerases may play a role in mediating mitochondrial toxicity. The
proposed project explores PrimPol, a recently characterized polymerase found in the mitochondria implicated in
replication restart and translesion synthesis, as a route for NRTI-associated toxicity. The project particularly
addresses this issue in the context of tenofovir, a widely used NRTI in modern treatments such as Atripla or
Truvada, in which the mechanism of nephrotoxicity has not yet been established. In the first aim, enzymatic
incorporation assays and X-ray crystallography will be used to determine the biochemical and structural basis
for tenofovir incorporation by PrimPol. In the second aim, PrimPol overexpression and shRNA knockdown strains
will be generated from HEK cells and renal proximal tubular epithelial cells to test the association of PrimPol with
mitochondrial toxicity that is observed in patients when treated with tenofovir. In conjunction, these aims will
establish the mechanism of toxicity of antiviral therapies and improve the development of nucleoside analog
inhibitors with better pharmacological profiles.

## Key facts

- **NIH application ID:** 9873815
- **Project number:** 5F31AI145454-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Vincent Duong
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $25,601
- **Award type:** 5
- **Project period:** 2019-02-01 → 2020-11-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873815

## Citation

> US National Institutes of Health, RePORTER application 9873815, Tenofovir inhibition of human mitochondrial polymerase PrimPol and mechanisms of antiviral therapy-driven nephrotoxicity (5F31AI145454-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9873815. Licensed CC0.

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