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Neuropsychological, Neurovirological and Neuroimmune Aspects of Abnormal GABAergic Transmission in HIV Infection.

ABSTRACT: The prevalence of HIV-associated neurocognitive disorders (HAND) remains high in patients with effective suppression of virus replication by combination antiretroviral therapy (cART). Several neurotransmitter systems were reported to be abnormal in HIV-infected patients, including the inhibitory GABAergic system, which mediates fine-tuning of neuronal processing and plays an essential role in cognitive functioning. To elucidate the role of abnormal GABAergic transmission in HAND, the expression of GABAergic markers was measured in 449 human brain specimens from HIV-infected patients with and without HAND. Using real-time polymerase chain reaction, immunoblotting and immunohistochemistry we found that the GABAergic markers were significantly decreased in most sectors of cerebral neocortex, the neostriatum, and the cerebellum of HIV-infected subjects. Low GABAergic expression in frontal neocortex was correlated significantly with high expression of endothelial cell markers, dopamine receptor type 2 (DRD2L), and preproenkephalin (PENK) mRNAs, and with worse performance on tasks of verbal fluency. Significant associations were not found between low GABAergic mRNAs and HIV-1 RNA concentration in the brain, the history of cART, or HIV encephalitis. Pathological evidence of neurodegeneration of the affected GABAergic neurons was not present. We conclude that abnormally low expression of GABAergic markers is prevalent in HIV-1 infected patients. Interrelationships with other neurotransmitter systems including dopaminergic transmission and with endothelial cell markers lend added support to suggestions that synaptic plasticity and cerebrovascular anomalies are involved with HAND in virally suppressed patients.

SUBMITTER: Buzhdygan T

PROVIDER: S-EPMC4848342 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Project description:We used Affymetrix U133A 2.0 chips to better understand transcriptional changes associated with HIV-1 infection and perinatal transmission in human PBMCS obtained from young adult mothers with infants in Botswana in vivo. HIV seropositive and drug naÃ¯ve samples:; GSM94333, GSM94334, GSM94335, GSM94336, GSM94337, GSM94338, GSM94340, GSM94342, GSM94343, GSM94345, GSM94351, GSM94353, GSM94354, GSM94355, GSM94357, GSM94358, GSM94360, GSM94361, GSM94362, GSM94364, GSM94365, GSM94367, GSM94369, GSM94370, GSM94378; HIV seronegative samples:; GSM92590, GSM92788, GSM92789, GSM92790, GSM92791, GSM92792, GSM92793, GSM92794, GSM92795, GSM92796, GSM92797, GSM92798, GSM92799, GSM92800, GSM92801, GSM92802, GSM92803, GSM92804, GSM92805, GSM92806; HIV seropositive transmitter mothers:; GSM94333, GSM94334, GSM94335, GSM94336, GSM94337, GSM94338, GSM94340, GSM94342, GSM94343, GSM94345, GSM94378; HIV seropositive nontransmitter mothers:; GSM94351, GSM94353, GSM94354, GSM94355, GSM94357, GSM94358, GSM94360, GSM94361, GSM94362, GSM94364, GSM94365, GSM94367, GSM94369, GSM94370 Experiment Overall Design: Total RNA was extracted from peripheral blood and processed for microarray hybridizations that were conducted using U133A 2.0 chips (Affymetrix, Santa Clara, CA). The 22,777 gene-probes were filtered based on presence/absence, resulting in data for 11,705 gene-probes. The array data sets were then analyzed for differential expression based on HIV status (seronegative, seropositive) and transmitter status (transmitter: TR, nontransmitter: NTR) using BADGE version 1.0, a computer program implementing a Bayesian approach to identify differentially expressed genes (Sebastiani et al, Nat.Gen, 2005). Once differentially expressed genes were identified by BADGE, the biologically enriched categories were identified, as recently described (Montano et al, Int Immunol, 2006), by implementing a stand-alone version of the EASE statistical software (Hosack et al, Genome Biol., 2003). Selected genes were validated using realtime reverse transcription PCR.

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Neuropsychological, Neurovirological and Neuroimmune Aspects of Abnormal GABAergic Transmission in HIV Infection.

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