# Nicotinic Acid Receptor Activation and Brain Proinflammatory Responses in HIV-1 Transgenic Rat

> **NIH NIH R01** · MOREHOUSE SCHOOL OF MEDICINE · 2020 · $355,000

## Abstract

Neurological complications occur commonly in HIV infection, with over 40% of individuals being at risk for
developing HIV-related neurocognitive impairment (NCI), with the numbers increasing in the era of effective
antiretroviral therapy (1). Factors that underlie the development of NCI include neuronal dysfunction due to
enhanced production of proinflammatory cytokines (e.g., TNF-α and IL-1β) and other inflammatory mediators
that are secreted by HIV-infected cells in the brain (2,3). Contributing to such responses is impairment
metabolism mediated by nicotinamide adenine dinucleotide (NAD), which is essential for normal mitochondrial
function and the production of energy substrates in cells. In this grant, we will analyze potential effects of
exposure to cigarette smoke (CS) and nicotine as co-factors for increasing the risk of NCI in HIV infected
individuals. Cigarette smoking has been shown to alter a number of innate and adaptive immune mechanisms
and can elicit cellular oxidative stress responses that can promote injury. Most marketed brands of cigarettes
contain varying amounts of nicotine. In smokers, CS causes a leukocytosis and, in HIV-infected individuals,
smoking is associated with higher plasma HIV viral loads and an increased mortality. It has been estimated
that over 40% of HIV+ individuals are cigarette smokers (6), a number that is twice the estimated prevalence of
smoking among adults in the general population (7). Nicotine, via activation of nicotinic acetylcholine receptors
(nAChR), promotes cigarette smoking through its addictive properties. By activating these receptors, nicotine
has been also shown to suppress immune activation and proinflammatory responses through direct effects on
immune cells as well as through pathways that are mediated by activation of nicotine receptors (8-10).
However, due to effects of HIV protein and with chronic nicotine exposure and upregulation of nAChR,
proinflammatory responses have been observed to increase, thereby potentially contributing to CNS damage
that occurs in the context of HIV infection. In previous studies in adult Lewis rats, we demonstrated that CS
exposure can result in marked inflammatory and oxidative stress responses in the brains of the exposed
animals (11). We have subsequently demonstrated that such effects can be also observed in HIV-1 transgenic
rats, with more prominent responses developing than what are observed in corresponding wild-type animals.
We also provide evidence that such responses can be driven by nicotine that is present in the CS. Activation of
nAChR can also regulate cellular levels of NAD and activation of associated metabolic pathways. The potential
effects of such activation in HIV infection and the generation of chronic inflammation in brain has not been
previously studied. The proposed studies will be performed in vivo utilizing the transgenic rat model as well as
in vitro utilizing primary astrocyte cultures that express the same HIV genes as the tr...

## Key facts

- **NIH application ID:** 9939495
- **Project number:** 5R01DA044908-04
- **Recipient organization:** MOREHOUSE SCHOOL OF MEDICINE
- **Principal Investigator:** WALTER ROYAL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $355,000
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939495

## Citation

> US National Institutes of Health, RePORTER application 9939495, Nicotinic Acid Receptor Activation and Brain Proinflammatory Responses in HIV-1 Transgenic Rat (5R01DA044908-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9939495. Licensed CC0.

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