# Anti-HIV NRTIs and the lysosomal toxicity

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $330,750

## Abstract

PROJECT SUMMARY
The nucleoside reverse transcriptase inhibitors (NRTIs) have potent activities against HIV, but their therapeutic
benefit in patients undergoing NRTI therapies is limited by significant adverse drug reactions (ADR), resulting
in poor patient compliance and compromised drug efficacy. Our group has recently described an indispensable
role of a lysosomal nucleoside transporter ENT3 in lysosomal homeostasis via deletion of ENT3 in mice.
Intriguingly, ENT3 KO mice manifest clinical phenotypes closely resembling NRTI ADR. The overall objective
of this application is to evaluate ENT3-loss driven lysosomal toxicity as a putative mechanism involved in the
chronic adverse sequelae of NRTIs. The central hypothesis of this proposal is that NRTIs that do not interfere
with ENT3-supported lysosomal homeostasis or the inclusion of lysosomal signaling agents will minimize the
occurrence of NRTI ADR. Aim 1 will evaluate the strategies to avoid NRTI toxicity without compromising drug
efficacy. Our working hypothesis for this aim is that disruption of interaction between ENT3 and NRTIs or the
inclusion of pharmacological agonists of lysosomal-autophagy pathway will mitigate the onset and severity of
NRTI ADR. The preliminary studies that demonstrate the involvement of the cell surface NRTI transporters
(e.g., ENT1, CNT) and not the lysosomal ENT3 for NRTI efficacy, the misregulation of the AMPK and mTOR
signaling axis in the Ent3-/- mice, and the functional rescue of multi-organ dysfunction in Ent3-/- mice using a
pharmacological AMPK activator AICAR; all support this aim. Aim 2 will elucidate the mechanism(s) of
occurrence of NRTI-specific ADR signs. Our working hypothesis for this aim is that NRTIs, when present at
clinically relevant blood concentrations, will inhibit the ENT3-regulated adult stem cell functions resulting in
disruption of tissue repair and regeneration. In addition, we hypothesize that NRTIs will differentially impact the
ENT3 function in adult tissues to bring distinct inflammatory, metabolic and degenerative changes that coupled
with stem cell alterations, will explain the clinically observed NRTI ADR signs. The preliminary studies that
demonstrate the transport of many ADR-producing NRTIs by ENT3, the inhibition of lysosomal adenosine
transport by NRTIs and the perturbation of lysosomal recycling of adenosine in Ent3-/- mice leading to adult
stem cell exhaustion, tissue inflammation and degeneration, and breaches of mesodermal tissue integrity,
which taken together supports this aim. The project will utilize biochemical and molecular approaches, novel
ENT3 probes, newly generated ENT3 mouse models, metabolomics, tissue engineering, pharmacophore
modeling, synthetic and screening procedures and PKPD to accomplish the goals. The successful completion
of the project will provide new insights into the mechanisms of occurrence of NRTI ADR and may have
translational benefit for optimizing treatments (such as long-term efficacy, adhe...

## Key facts

- **NIH application ID:** 10273397
- **Project number:** 1R01GM143217-01
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** RAJGOPAL GOVINDARAJAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $330,750
- **Award type:** 1
- **Project period:** 2021-09-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10273397

## Citation

> US National Institutes of Health, RePORTER application 10273397, Anti-HIV NRTIs and the lysosomal toxicity (1R01GM143217-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10273397. Licensed CC0.

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