# The impact of naltrexone treatment on opioid-induced immune and viral dysregulation during HIV-infection

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $735,253

## Abstract

PROJECT SUMMARY
Chronic opioid use among people living with HIV (PLHIV) is an on-going public health crisis. The interplay
between opioids and HIV may accelerate HIV-associated immune dysregulation, chronic inflammation and
coagulopathy, and predispose to AIDS and non-AIDS related mortality and morbidities. Published data from in
vitro and animal models demonstrate that, in addition to their interactions with opioid receptors, opioids directly
bind and activate Toll-like Receptor-4 (TLR-4), promote intestinal damage and microbial translocation, interfere
with regulation of lipopolysaccharide (LPS)-induced inflammation, and facilitate HIV replication. Our own
preliminary data support that opioid use is associated with advanced immune activation and dysregulated
responses to LPS among PLHIV. We hypothesize that opioid exposure disrupts homeostatic anti-inflammatory
miRNAs that normally limit TLR-4 mediated monocyte activation in response to LPS, leading to chronic innate
immune activation and dysfunction. We propose that opioid exposure will be associated with evidence of
advanced intestinal permeability, HIV-associated T cell activation and exhaustion, coagulopathy, and
compromised antiviral capacity. In this proposal, we will capitalize on our access to longitudinal clinical
samples from PLHIV who also suffer from opioid-use disorders (HIV+/OUD+), who are participating in an
independent phase IIb randomized clinical trial (CTN-067) to determine optimal management of combined HIV
infection and OUD. Trial participants will receive antiretroviral therapy (ART) plus 6 months of OUD therapy
with either 1) the long-acting opioid-antagonist extended release naltrexone (XR-NTX); or 2) treatment-as-
usual (TAU) with opioid-agonists. Based on published findings from in vitro and animal models, we propose
that XR-NTX will be associated with significant reductions in gut permeability, immune activation and
exhaustion, coagulopathy, and gains in T cell anti-viral capacity (Aim 1); will restore miRNAs that normally
regulate LPS-induced immune activation (Aim 2); and will promote early viral control and reduction of the
inducible HIV reservoir (Aim 3). To address these aims, we will use samples collected from CTN-067 trial
participants (N=350), as well as a reference cohort of PLHIV with no history of substance dependency or
opioid exposure (HIV+/OUD-; N=100). We will employ advanced techniques including: an ultrasensitive
electrochemiluminescence-based platform to measure plasma cytokines; next generation sequencing (NGS) of
miRNA and mRNA from resting and LPS-stimulated monocytes; a Tat/rev Induced Limiting Dilution Assay
(TILDA) to quantify seeding of the inducible provirus reservoir; and a novel flow cytometry assay to quantify
CD4+ T cell subsets that contain provirus expressing the gag protein and new budding cell surface virions. We
hope to identify an OUD treatment strategy that simultaneously ameliorates immune dysregulation and
promotes viral control;...

## Key facts

- **NIH application ID:** 9978796
- **Project number:** 5R01DA046229-03
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Christina Louise Lancioni
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $735,253
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978796

## Citation

> US National Institutes of Health, RePORTER application 9978796, The impact of naltrexone treatment on opioid-induced immune and viral dysregulation during HIV-infection (5R01DA046229-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9978796. Licensed CC0.

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