# NLRP inflammasome directed activation of the innate immune system produces synaptic damage in EcoHIV infected mice self-administering fentanyl

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $563,007

## Abstract

ABSTRACT
People living with HIV (PLWH) have higher rates of drug addiction compared with uninfected populations, and
often show faster rates of disease progression, including early and rapidly progressing cognitive impairments.
We have previously demonstrated that synaptic damage resulting from acute morphine administration self-
repairs during drug withdrawal. These repair mechanisms were not active in gp120 transgenic mice, and synaptic
repair failed during drug withdrawal. Although these observations in addition to a number of other studies that
have demonstrated interactions of morphine with HIV that ultimately reduce dendritic spine density, the precise
mechanisms for these interactions are not understood. Our preliminary findings suggests that the initial dendritic
damage induced by morphine involves activation of a non-canonical Nucleotide-binding oligomerization domain,
Leucine rich Repeat and Pyrin domain containing (NLRP) inflammasome pathway in astrocytes that facilitates
the release of EVs carrying complement C3. This complement protein is opsonized in dendritic spines and targets
them for elimination by phagocytosis. The removal of morphine stops the shedding of complement C3 from
astrocytes, and dendritic spines can self-repair. However, in the setting of viral infection there is a sustained
activation of pattern recognition receptors on microglia with chronic activation of the classical NLRP
inflammasome pathway that maintains a state of persistent inflammation, This chronic inflammatory state
disallows dendritic spines to self-repair. Here we propose to use primary cell culture, EcoHIV infected mice, and
conditional transgenic systems to test the hypothesis that interactions between TLRs, the inflammasome, and
the complement system contribute to neuronal damage in PLHW who abuse opiates.
.

## Key facts

- **NIH application ID:** 10832647
- **Project number:** 5R01DA052272-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Norman J Haughey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $563,007
- **Award type:** 5
- **Project period:** 2020-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10832647

## Citation

> US National Institutes of Health, RePORTER application 10832647, NLRP inflammasome directed activation of the innate immune system produces synaptic damage in EcoHIV infected mice self-administering fentanyl (5R01DA052272-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10832647. Licensed CC0.

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