# Microbial Dysbiosis and TLR2 Activation Contribute to Immune Activation, Inflammation and HIV Persistence in the Context of Opioid Abuse Despite ART Therapy

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $509,400

## Abstract

Project Summary
Persistent inflammation and immune activation drive HIV disease progression despite ART therapy. However,
the underlying mechanisms are currently speculative and not clearly delineated. Gut leakiness and microbial
translocation are hallmarks of HIV disease progression. Interestingly, chronic opioid abuse is also well
documented to induce gut leakiness and sustained microbial translocation. Increasing number of studies
strongly support the concept that the gut microbiota, play a significant role in maintaining gut homeostasis and
gut barrier function. Although a few studies have correlated the host microbiome in HIV infected patients with
gut barrier function disruption and microbial translocation, the consequence in the context of antiretroviral
treatment (ART) still remains largely unexplored. There is no data on the consequences of an altered
microbiome with immune activation and viral persistence in HIV patients on ART therapy in the context of
opioid abuse. Although most studies measure endotoxin levels and bacterial products associated with gram-
negative bacterial infection with inflammation and HIV disease progression, recent studies clearly show a
distinct enrichment and prevalence of gram positive bacterial communities in HIV infected patients when
compared to normal healthy individuals. Our preliminary data show significant expansion and translocation of
gram positive bacterial communities in HIV infected BLT mice which are further exacerbated in the context of
opioid treatment. Our central hypothesis is that microbial dysbiosis with preferential expansion of Gram positive
(G+) bacterial communities in HIV infected individuals and HIV infected individuals that are opioid abusers lead
to G+ bacterial translocation, TLR2/TLR4 activation and is the driving mechanism for immune cell activation
and sustained inflammation contributing to disease progression and preventing the restoration of normal health
in HIV-infected individuals that are opioid drug abusers. We will further investigate if treatment with ART
restores homeostasis or exacerbates dysbiosis. We will test our hypothesis using NSG-BLT humanized
murine model of HIV and HIV in context of substance abuse and ART. In Specific Aim 1 we will
determine the role of microbial dysbiosis, expansion of gram-positive bacterial communities and gut leakiness
with immune activation and viral persistence. In Specific Aim 2 we will determine that activation of TLR-2 in
immune cells and gut epithelial cells results in immune activation and viral persistence following HIV infection
and in the context of opioid drug abuse and ART treated humanized mice. In Specific Aim 3 we will determine
that combination therapy with Probiotics and TLR2 antagonists will restore gut homeostasis and attenuate
immune activation thereby delaying HIV disease progression in the context of opioid abuse and ART. The
results from these studies will allow for the development of new adjunct therapeutic strategi...

## Key facts

- **NIH application ID:** 9939492
- **Project number:** 5R01DA044582-04
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Sabita Roy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $509,400
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939492

## Citation

> US National Institutes of Health, RePORTER application 9939492, Microbial Dysbiosis and TLR2 Activation Contribute to Immune Activation, Inflammation and HIV Persistence in the Context of Opioid Abuse Despite ART Therapy (5R01DA044582-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9939492. Licensed CC0.

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