Gene expression changes consistent with neuroAIDS and impaired working memory in HIV-1 transgenic rats

Abstract

BackgroundA thorough investigation of the neurobiology of HIV-induced neuronal dysfunction and its evolving phenotype in the setting of viral suppression has been limited by the lack of validated small animal models to probe the effects of concomitant low level expression of multiple HIV-1 products in disease-relevant cells in the CNS.ResultsWe report the results of gene expression profiling of the hippocampus of HIV-1 Tg rats, a rodent model of HIV infection in which multiple HIV-1 proteins are expressed under the control of the viral LTR promoter in disease-relevant cells including microglia and astrocytes. The Gene Set Enrichment Analysis (GSEA) algorithm was used for pathway analysis. Gene expression changes observed are consistent with astrogliosis and microgliosis and include evidence of inflammation and cell proliferation. Among the genes with increased expression in HIV-1 Tg rats was the interferon stimulated gene 15 (ISG-15), which was previously shown to be increased in the cerebrospinal fluid (CSF) of HIV patients and to correlate with neuropsychological impairment and neuropathology, and prostaglandin D2 (PGD2) synthase (Ptgds), which has been associated with immune activation and the induction of astrogliosis and microgliosis. GSEA-based pathway analysis highlighted a broad dysregulation of genes involved in neuronal trophism and neurodegenerative disorders. Among the latter are genesets associated with Huntington’s disease, Parkinson’s disease, mitochondrial, peroxisome function, and synaptic trophism and plasticity, such as IGF, ErbB and netrin signaling and the PI3K signal transduction pathway, a mediator of neural plasticity and of a vast array of trophic signals. Additionally, gene expression analyses also show altered lipid metabolism and peroxisomes dysfunction. Supporting the functional significance of these gene expression alterations, HIV-1 Tg rats showed working memory impairments in spontaneous alternation behavior in the T-Maze, a paradigm sensitive to prefrontal cortex and hippocampal function.ConclusionsAltogether, differentially regulated genes and pathway analysis identify specific pathways that can be targeted therapeutically to increase trophic support, e.g. IGF, ErbB and netrin signaling, and reduce neuroinflammation, e.g. PGD2 synthesis, which may be beneficial in the treatment of chronic forms of HIV-associated neurocognitive disorders in the setting of viral suppression.

Cigarette smoke and nicotine effects on brain proinflammatory responses and behavioral and motor function in HIV-1 transgenic rats

“…In the studies reported here, where the rats were exposed to nicotine at a slightly higher dose and for a longer duration, as well as to potentially additional stress from behavioral and motor testing, we observed that TNF-α, IL-1, and IL-6 gene expression levels were all increased by smoke exposure in HIV1Tg rat brains, whereas IL-6 gene expression was not increased by the exposures in F344 rat brains, suggesting the existence of a greater susceptibility to such exposures for the transgenic rat. This is consistent with our previous findings where increased proinflammatory responses were demonstrated both systemically and in brains from the transgenic versus the wild-type animals and with other studies that demonstrated the presence of increased astrocyte and microglial activation the brains of transgenic rats that were produced on a Sprague-Dawley rat background (Repunte-Canonigo et al 2014). Also, analysis of peripheral blood immune cell phenotypes in HIV1Tg rats showed increased numbers of circulating cytotoxic T cells as well as increased percentages of helper T cells and monocytes as compared to F344 rats (Abbondanzo and Chang 2014), although helper T cells and monocytes can be functionally either proinflammatory or anti-inflammatory (Geissmann et al 2008).…”

Characterization of neuropathology in the HIV-1 transgenic rat at different ages

“…We’ve also previously described in vivo imaging findings in this animal model suggestive of neuropathology using both magnetic resonance imaging (MRI) and positron emission tomography (PET) (Lee et al, 2014a, Lentz et al, 2014). Although there have been previous meticulous studies examining certain aspects of brain pathology in this animal model (Repunte-Canonigo et al, 2014, Royal et al, 2012), the exact neuropathology with respect to age and whether viral proteins are expressed in the CSF have not been thoroughly characterized.…”

The HIV-1 transgenic rat model of neuroHIV

“…Although rodents engage in species-typical exploratory behavior, like humans, they utilize cognitive information such as memory of locations recently visited to guide their behavior. The altered exploratory behavior in HIV-1Tg rats could reflect similar deficits in cognition (Repunte-Canonigo 2014) that underlies the decline in everyday functioning that defines HIV-associated mild neurocognitive disorder in human HIV patients.…”

“…In a more structured test environment, such as a T-maze, rats have a very strong tendency to alternate arm choices as they explore across trials. This spontaneous alternation behavior is significantly reduced in HIV-1Tg rats (Repunte-Canonigo 2014). …”

“…Thus, spontaneous alternation is supported by the capacity of working memory. In a recent study, HIV-1Tg rats showed a marked decrease in spontaneous alternation in a T-maze compared to control animals, indicating disruption in working memory (Repunte-Canonigo 2014). Moreover, this deficit was correlated with the expression of HIV-1 proteins in the HIP as well as gene expression that is consistent with neuroHIV.…”