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.Electronic supplementary materialThe online version of this article (doi:10.1007/s11481-016-9652-2) contains supplementary material, which is available to authorized users.
Highlights
The prevalence of HIV-associated neurocognitive disorders (HAND) is substantial in patients treated with combination antiretroviral therapy (cART) (McArthur et al 2010)
While the frequency of HIVE declined in cART-treated patient cohorts to below 5 %, the prevalence of HAND remains as high as 50 %
Neurovirological and brain gene expression data both show that the overwhelming majority of patients with HAND taking cART do not have HIVE, and they are not likely to harbor a high concentration of replicating HIV in the CNS (Gelman et al 2012a, 2013)
Summary
The prevalence of HIV-associated neurocognitive disorders (HAND) is substantial in patients treated with cART (McArthur et al 2010). Data from the cART era, are far less supportive of the putative association between HAND and HIVE (Gelman 2015). While the frequency of HIVE declined in cART-treated patient cohorts to below 5 %, the prevalence of HAND remains as high as 50 %. Neurovirological and brain gene expression data both show that the overwhelming majority of patients with HAND taking cART do not have HIVE, and they are not likely to harbor a high concentration of replicating HIV in the CNS (Gelman et al 2012a, 2013). The pathophysiology of HAND remains poorly understood, especially when virus replication is suppressed with cART
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