# Molecular Pathways of Innate Immunity and Substance Abuse in NeuroHIV

> **NIH NIH R61** · RUSH UNIVERSITY MEDICAL CENTER · 2023 · $423,415

## Abstract

PROJECT SUMMARY
 A significant percentage of people living with HIV/AIDS (PLWH) exhibit HIV associated neurocognitive
disorders (HAND). With the development and improvement of combination antiretroviral therapies (cART) there
was a substantial decrease of the death and morbidity rates of PLWH. HAND and neuroinflammation are
exacerbated by Methamphetamine (Meth) abuse. PLWH abusing Meth present a high prevalence of chronic
neuroinflammation and the cellular mechanism(s) that drive such inflammation have not been entirely defined.
 Certain models of neuroinflammation define inter-cellular cytokine signaling as a major player in
neuroinflammation. These models propose that activation of microglia results in the production of inflammatory
cytokines and metabolites that are recognized by astrocytes, leading to a modification from non-reactive
astrocytes to a range of pro-inflammatory or repair phenotypes. In this proposal we aim to identify the molecular
mechanisms that trigger the activation of intracellular innate immunity in microglia and astrocytes in the context
of NeuroHIV and Meth, and characterize the cellular crosstalk between HIV infected and non-infected brain cells
under physiological concentrations of cART.
 Our preliminary data from gene expression and microscopy of innate sensing immune complexes points to
an activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway in
microglia with Meth and HIV infection. Thus, we hypothesize that HIV-triggered activation of the cGAS/STING
pathway leads to episodes of chronic neuroinflamation. We also hypothesize that Meth-mediated DNA damage
is additive to the activation of the inflammation pathway. In the R61 phase, we aim to determine the impact of
HIV post-entry events and Meth-mediated DNA damage on innate immune sensing of glial cells. During the R33
phase, we will characterize the biological consequences of HIV/Meth-mediated innate sensing to brain organoids
under brain physiologic cART concentrations. We aim to assess the potential of cGAS/STING antagonists to
reduce neuroinflammation in the context of HIV/Meth. We will carry out an experimental plan using functional
assays, cyclic multiplex immunofluorescence and super-resolution fluorescence imaging, machine learning
analysis, next-generation sequencing, and multiplexed cytokine profiling in iPSC-derived microglia, astrocytes,
cerebral brain organoids and a chimeric human/mouse animal model.
 These studies will define the activation of HIV/Meth-mediated innate immunity in cells from the brain that are
known to be infected by HIV and the impact of this activation in the disruption of normal brain homeostasis by
inflammatory processes. At the heart of this proposal is the clarification and identification of the
mechanism(s) that drive and/or contribute to persistent neuroinflammation by HIV and Meth under cART
that culminate in HAND. Knowledge gained from this research plan can inform therapeutic potential...

## Key facts

- **NIH application ID:** 10814534
- **Project number:** 1R61DA058348-01A1
- **Recipient organization:** RUSH UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Joao Filipe Inacio Mamede
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $423,415
- **Award type:** 1
- **Project period:** 2023-09-30 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814534

## Citation

> US National Institutes of Health, RePORTER application 10814534, Molecular Pathways of Innate Immunity and Substance Abuse in NeuroHIV (1R61DA058348-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10814534. Licensed CC0.

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