Since the introduction of highly-active anti-retroviral therapy, HIV patients survive and age, but even individuals with well controlled infection remain vulnerable to the development of HIV-associated neurocognitive disorders. Aging itself is the major risk factor for cognitive decline in uninfected individuals. Thus, the question arises whether HIV-1 and aging interact to accelerate neuronal injury and cognitive decline. AIDS patients and mice expressing HIV-1 gp120 as transgene in the brain (gp120tg) share several neuropathological hallmarks, such as a reduction of neuronal dendrites and pre-synaptic terminals, and glial cell activation. However, behavioral deficits, such as memory impairment, are only detected in the mouse model at around 12 month of age, suggesting that the viral protein and aging may cooperate in the deterioration of neurocognitive function. For the present study we collected brain tissue of HIV gp120tg mice and non-transgenic littermate controls at 1.5, 4, 6, 12 and 20 month of age and isolated RNA. For each time point and genotype gene expression in 3 to 5 animals was investigated using microarrays (MouseWG-6 v2.0 Expression BeadChip, Illumina, San Diego, CA).The manufacturer’s BeadArray Reader and software were employed to collect primary data. Quality control, normalization, detection of expressed genes and analysis of differentially expressed genes was accomplished using Beadstudio, followed by Bioconductor and GeneSpring software. Resulting gene lists were further analyzed using Ingenuity Pathway Analysis (IPA) and Nextbio software packages. Expression of about 21,500 genes was detected. Two-way ANOVA (corrected p-value cut-off: 0.05) indicated that genotype (HIVgp120tg versus control) significantly affected expression of 2852 genes, age 16,067 genes and an interaction of genotype and age 2,629 genes. 322 genes were affected by all three parameter. Sixty of these genes have been linked to neurological (10), inflammatory (16) or immunological disease (12) or an inflammatory response (22; IPA), and thus confirm results of previous neuropathological studies. Moreover, 53 of the genes were implicated in age-dependent impairment of spatial memory (p value 3.30E-6, Nextbio), matching observations during behavioral testing. Moreover, numerous genes differentially expressed in HIVgp120tg mice have also been reported for the brains of neurocognitively impaired AIDS patients and SIV-infected non-human primates. Supported by NIH grants R01 NS050621 and R01 MH087332 (to M.K.).
Genome-wide analysis of gene expression in brains of HIV gp120 transgenic mice reveals differential regulation due to genotype and age
RUSSO, Rossella;
2011-01-01
Abstract
Since the introduction of highly-active anti-retroviral therapy, HIV patients survive and age, but even individuals with well controlled infection remain vulnerable to the development of HIV-associated neurocognitive disorders. Aging itself is the major risk factor for cognitive decline in uninfected individuals. Thus, the question arises whether HIV-1 and aging interact to accelerate neuronal injury and cognitive decline. AIDS patients and mice expressing HIV-1 gp120 as transgene in the brain (gp120tg) share several neuropathological hallmarks, such as a reduction of neuronal dendrites and pre-synaptic terminals, and glial cell activation. However, behavioral deficits, such as memory impairment, are only detected in the mouse model at around 12 month of age, suggesting that the viral protein and aging may cooperate in the deterioration of neurocognitive function. For the present study we collected brain tissue of HIV gp120tg mice and non-transgenic littermate controls at 1.5, 4, 6, 12 and 20 month of age and isolated RNA. For each time point and genotype gene expression in 3 to 5 animals was investigated using microarrays (MouseWG-6 v2.0 Expression BeadChip, Illumina, San Diego, CA).The manufacturer’s BeadArray Reader and software were employed to collect primary data. Quality control, normalization, detection of expressed genes and analysis of differentially expressed genes was accomplished using Beadstudio, followed by Bioconductor and GeneSpring software. Resulting gene lists were further analyzed using Ingenuity Pathway Analysis (IPA) and Nextbio software packages. Expression of about 21,500 genes was detected. Two-way ANOVA (corrected p-value cut-off: 0.05) indicated that genotype (HIVgp120tg versus control) significantly affected expression of 2852 genes, age 16,067 genes and an interaction of genotype and age 2,629 genes. 322 genes were affected by all three parameter. Sixty of these genes have been linked to neurological (10), inflammatory (16) or immunological disease (12) or an inflammatory response (22; IPA), and thus confirm results of previous neuropathological studies. Moreover, 53 of the genes were implicated in age-dependent impairment of spatial memory (p value 3.30E-6, Nextbio), matching observations during behavioral testing. Moreover, numerous genes differentially expressed in HIVgp120tg mice have also been reported for the brains of neurocognitively impaired AIDS patients and SIV-infected non-human primates. Supported by NIH grants R01 NS050621 and R01 MH087332 (to M.K.).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
