Immunomodulation of nicotine in HIV-1Tg rat brain - Project Summary:
As one of the key active ingredients of tobacco smoke, nicotine exerts its actions primarily on the nicotinic
acetylcholine receptors (nAChRs), which are expressed on neurons, microglia, and other cells in the central
nervous system (CNS). Activation of nAChRs by nicotine has various potential therapeutic immune benefits,
including modulation of inflammatory responses, maintenance of immune homeostasis, and regulation of
expression of pro- and anti-inflammatory factors. However, smokers have a higher rate of HIV disease
progression and behavioral and cognitive complications, with differences seen between male and female
smokers. It has been suggested that prolonged exposure to nicotine in HIV patients through cigarette smoking
might decrease the expression and desensitize the activation of nAChRs, which could dampen nicotine's ability
to mediate immune responses. During the past several years, we have conducted a series of behavioral and
molecular studies using a rodent HIV-1 transgenic (HIV-1Tg) rat model to study various medical issues,
including immunity, associated with HIV patients receiving combined anti-retroviral therapy (cART). We used
this HIV-transgenic rat model to determine the effects of nicotine on brain function in the presence of HIV-1
proteins and found that chronic treatment with nicotine can restore the expression of many genes altered by
the HIV-1 viral proteins in signaling pathways involved in immunity and other neuronal systems. In addition, we
found that expression of various nAChR subunits, especially α6, β3, and β4, and immune-related genes, such
as interferon regulatory factor 7 (IRF7) and interleukin-1α (IL-1α), differ greatly in HIV-1Tg rats compared with
F344 controls. Our findings indicate that HIV-1 proteins greatly impact CNS immunity as well as nAChR
function and alter the responsiveness to nicotine in certain immune-related and nAChR-mediated signaling
pathways. Based on these findings, we hypothesize that there are significant interactions between nicotine and
HIV-1 proteins that affect the immune response to nicotine in the brain of HIV-1-positive individuals. To test this
hypothesis, we propose the following three aims. Aim 1 is to determine the interactive effects of nicotine and
HIV viral proteins on microglia and macrophages in the brain as well as cytokine production in the blood and
brain of the HIV-1Tg rat. Aim 2 is to compare the interactive effects of nicotine and HIV-1 viral proteins on
gene expression in three brain regions of male and female HIV-1Tg rats using RNA-seq analysis. Aim 3 is to
characterize specific genes and pathways that mediate the effects of the interaction between nicotine and HIV-
1 viral proteins using various molecular techniques, including CRISPR gene editing. The proposed studies
represent the first application of next-generation sequencing technique in combination with conventional
molecular approaches to investigate the modulatory effects of chronic use of nicotine on CNS immunity in the
presence of HIV-1 viral proteins. By combining both genomic and molecular approaches, our studies will be
comprehensive and free of subjective bias and assure the value of the data for the development of new
strategies for treating HIV-1 patients who use nicotine.
