Abstract
The noninfectious HIV-1 transgenic (HIV-1Tg) rat was developed as a model of AIDs-related pathology and immune dysfunction by manipulation of a noninfectious HIV-1gag-pol virus with a deleted 3-kb SphI-MscI fragment containing the 3′ -region of gag and the 5′ region of pol into F344 rats. Our previous studies revealed significant behavioral differences between HIV-1Tg and F344 control rats in their performance in the Morris water maze and responses to psychostimulants. However, the molecular mechanisms underlying these behavioral differences remain largely unknown. The primary goal of this study was to identify differentially expressed genes and enriched pathways affected by the gag-pol-deleted HIV-1 genome. Using RNA deep sequencing, we sequenced RNA transcripts in the prefrontal cortex, hippocampus, and striatum of HIV-1Tg and F344 rats. A total of 72 RNA samples were analyzed (i.e., 12 animals per group × 2 strains × 3 brain regions). Following deep-sequencing analysis of 50-bp paired-end reads of RNA-Seq, we used Bowtie/Tophat/Cufflinks suites to align these reads into transcripts based on the Rn4 rat reference genome and to measure the relative abundance of each transcript. Statistical analyses on each brain region in the two strains revealed that immune response- and neurotransmission-related pathways were altered in the HIV-1Tg rats, with brain region differences. Other neuronal survival-related pathways, including those encoding myelin proteins, growth factors, and translation regulators, were altered in the HIV-1Tg rats in a brain region-dependent manner. This study is the first deep-sequencing analysis of RNA transcripts associated the HIV-1Tg rat. Considering the functions of the pathways and brain regions examined in this study, our findings of abnormal gene expression patterns in HIV-1Tg rats suggest mechanisms underlying the deficits in learning and memory and vulnerability to drug addiction and other psychiatric disorders observed in HIV-positive patients.
Highlights
Human immunodeficiency virus-1 (HIV-1) infection involves the actions of HIV-1 viral proteins on targeted cells of the immune system, such as macrophages and T-lymphocytes [1,2,3,4,5,6]
We selectively examined interferon regulatory factor 7 (Irf7) and Nucleophosmin (Npm1) with the same RNA samples used for RNA-seq analysis, considering they are the only genes showing strain differences in all the three brain regions based on the deep sequencing analysis results
We found 197, 154, and 171 differentially expressed genes in the prefrontal cortex (PFC), HIP, and STR regions, respectively, in HIV-1 transgenic (HIV-1Tg) rats compared to F344 rats
Summary
Human immunodeficiency virus-1 (HIV-1) infection involves the actions of HIV-1 viral proteins on targeted cells of the immune system, such as macrophages and T-lymphocytes [1,2,3,4,5,6]. Like the peripheral immune system, the central nervous system (CNS) is highly vulnerable to HIV-1 infection. The neuropathology resulting from HIV-1 infection is characterized by progressive cognitive decline, motor dysfunction, striatal pathology, and gliosis [13,14]. Highly active anti-retroviral therapy (HAART) leads to a temporary reversal of HIV dementia [15,16,17], both the HIVassociated neurocognitive disorders (HAND) and HIV-associated dementia (HAD) are resistant to HAART and become more severe as the lifespan of HIV-1-infected patients is prolonged [18]. A thorough understanding of how HIV-1 infection induces cognitive dysfunction is greatly needed. Given that HAART can inhibit viral entry and replication without eliminating the viral proteins [19,20,21,22,23], the clinical challenge in this post-HAART era is to determine the effects of the persistent presence of HIV viral proteins in the host [20,24,25]
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