RNA Deep Sequencing Analysis Reveals That Nicotine Restores Impaired Gene Expression by Viral Proteins in the Brains of HIV-1 Transgenic Rats

Abstract

Persons infected with HIV-1 often develop neurologic disorders despite receiving highly active anti-retroviral therapy. Although the underlying mechanism is largely undetermined, our previous RNA-seq-based study showed that the expression of many genes was altered in the central nervous system (CNS) of HIV-1 transgenic (HIV-1Tg) rats. Because nicotine, a natural agonist of nicotinic acetylcholine receptors, exhibits a neuroprotective effect, we presently tested the hypothesis that nicotine restores the expression of altered genes in the CNS of HIV-1Tg rats. Adult male HIV-1Tg and F344 control strain rats were injected with either nicotine (0.25 mg/kg) or saline subcutaneously twice a day for 17 days. Gene expression in the prefrontal cortex (PFC), dorsal hippocampus (HIP), and dorsal striatum (STR) was evaluated using the RNA deep sequencing technique. We found that about 20% of the altered genes in the HIV-1Tg rat were affected by nicotine in each brain region, with the expression of most restored. Analysis of the restored genes showed distinct pathways corrected by nicotine in different brain regions of HIV-1Tg rats. Specifically, the two most significantly restored pathways were Wnt/β-catenin signaling and ephrin B signaling in the PFC, cAMP-responsive element-binding protein (CREB) signaling and glutathione metabolism pathway in the HIP, and tricarboxylic acid (TCA) cycle and calcium signaling in the STR. Together, our findings indicate that cholinergic modulators such as nicotine have beneficial effects on HIV-1-induced neurologic deficits.

The HIV-1 transgenic rat model of neuroHIV

“…Deep-sequencing analysis of RNA transcripts revealed differentially altered gene expression in cortical, HIP, and STR brain regions in the HIV-1Tg rat compared to control (Cao, Wang et al 2013). When treated with nicotine, approximately 20% of the altered gene expression in each brain region is restored (Li, Cao et al 2013).…”

“…In a subsequent study, RNA deep-sequencing analysis was also used to determine whether the altered gene expression observed in the HIV-1Tg rats could be corrected by nicotine. Cao et al (2013) found that nicotine restores expression of about 20% of the altered genes in each brain region and modulates distinct pathways in different brain regions (Cao, Wang et al 2013). The most significantly restored pathways are the Wnt/b catenin signaling and ephrin B signaling pathways in the PFC, cAMP-responsive element-binding protein (CREB) signaling and glutathione metabolism pathways in the HIP, and the tricarboxylic acid (TCA) cycle and calcium signaling pathway in the STR.…”

Modulation Effect of HIV-1 Viral Proteins and Nicotine on Expression of the Immune-Related Genes in Brain of the HIV-1 Transgenic Rats

“…Nicotine has a similar effect on oxidative stress in the striatum and also restores the function of the tricarboxylic acid cycle in this brain region. This study demonstrated that nicotine has the ability to regulate a number of neurodegenerative effects of HIV-1 viral proteins in various brain regions (Cao et al, 2013). …”

“…Specifically for this HIV-1Tg rat model, we found that the expression a significant number of genes related to neuroprotective function and Wnt/β-catenin is restored by treatment with nicotine (Cao et al, 2013). More specifically, in the PFC, genes related to Wnt/β-catenin signaling are restored to a level comparable to F344 control rats.…”

NeuroHIV and Use of Addictive Substances

“…In a subsequent study, RNA deepsequencing analysis was also used to determine whether the altered gene expression observed in the HIV-1Tg rats could be corrected by nicotine. Cao et al (2013) found that nicotine restores expression of about 20% of the altered genes in each brain region and modulates distinct pathways in different brain regions. The most significantly restored pathways are the Wnt/b catenin signaling and ephrin B signaling pathways in the PFC, cAMPresponsive element-binding protein signaling and glutathione metabolism pathways in the HIP, and the tricarboxylic acid cycle and calcium signaling pathway in the STR.…”