# Mechanisms underlying dysregulated neuroimmune signaling and neuronal dysfunction in HIV (+) individuals with cART and cocaine

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2021 · $362,188

## Abstract

Abstract:
Sustained neuroinflammation & synaptodendritic injury are the two hallmark features underlying NeuroHIV.
Factors contributing to these pathological changes include low-level residual HIV replication/HIV proteins and/or
toxicity of cART itself. It is well-recognized that drug abuse, specifically cocaine abuse, is a common comorbidity
of HIV infection. Intriguingly, cocaine has also been shown to exacerbate neuroinflammation either through its
direct effects on immune cells, such as microglia and/or by decreasing the effectiveness of cART. It can thus be
envisioned that within the CNS, combinations of HIV proteins, abused drugs and cART create a toxic milieu
promoting exacerbated neuroinflammation and abnormal glial-neuronal cross-talk via the pro-inflammatory
mediators. The detailed molecular pathways underlying the dysregulated neuroimmune signaling and
subsequent synaptodendritic injury, however, remain elusive. Our preliminary studies have demonstrated that:
1) HIV TAT can increase microglial activation via the NLRP3 inflammasome signaling; 2) cocaine activates
microglia via the dysregulated autophagy pathway, & 3) Combination of clinically used antiretroviral cocktail (TFV,
FTC, DTG) impaired microglial lysosome functions leading to their activation. Furthermore, we also
demonstrated that IL1β, product of the NLRP3 inflammasome activation pathway, upregulated the glutamate
receptor ionotropic NMDAs (GRINS) and concomitantly decreased spine density in primary neurons. The
premise of this application thus is that combinations of HIV TAT, cocaine & ARVs can activate microglia via
the NLRP3 inflammasome & autophagy pathways, and that the increased release of IL1β. In turn,
contributes to neuronal dysfunction. Using both in vitro and in vivo (HIV transgenic rats) approaches we will
test the hypothesis via three specific aims - SA1: Investigate the molecular mechanism(s) underlying TAT,
cocaine, & ARVs (3 drug regimen)-mediated activation of microglia in vitro; SA2: Investigate the molecular
mechanism(s) underlying IL1β-induced neuronal excitotoxicity & SA3: Validate in vivo the changes in NLRP3
inflammasome and autophagy signaling and also lncRNA malat1/NF-κB/GRINs axis in conjunction with
behavioral deficits in HIV-Tg rats administered cocaine and cARV. Two experienced PIs (Drs. Guo & Buch) will
co-lead this project to accomplish the proposed goals. This R01 application, in response to RFA-MH-18-610
titled “Altered neuronal circuits, receptors and networks in HIV-induced Central Nervous System (CNS)
dysfunction,” aims to explore the molecular mechanisms underlying how the dysregulated neuroimmune
signaling caused by HIV proteins, drugs of abuse, & cRAT impacts the function of neuronal receptors.

## Key facts

- **NIH application ID:** 10241327
- **Project number:** 5R01DA047156-04
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Shilpa J Buch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $362,188
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241327

## Citation

> US National Institutes of Health, RePORTER application 10241327, Mechanisms underlying dysregulated neuroimmune signaling and neuronal dysfunction in HIV (+) individuals with cART and cocaine (5R01DA047156-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10241327. Licensed CC0.

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