HAND is a common complication of HIV-1 infection in the nervous system presenting a varied spectrum of clinical manifestations with cognitive, motor and behavioral symptoms. Currently three conditions of increasing severity are recognized as components of HAND: HIV-1-associated asymptomatic neurocognitive impairment, HIV-1-associated mild neurocognitive disorders (MND), and HIV-1-associated dementia (HIV-D or HAD) 
. HAND remains prevalent in populations with access to highly active ART, despite the efficacy of these therapies in controlling viral load and ameliorating viral load-associated clinical and neuroradiologic abnormalities 
. By some accounts, up to 50% of HIV-1-infected individuals will develop some form of HAND regardless of access to currently available ART 
. Under ART, HAND has became milder, its course more protracted and variable in symptoms, and it now overlaps with aging processes and potentially with other neurodegenerative diseases in AIDS patients 
. The etiology of persistent cognitive deficits in patients on ART remains unclear. Studies of cerebrospinal fluid from individuals with HAND have sometimes supported contradictory conclusions; in the absence of viral replication, some authors observe associations among dementia, abnormal neurometabolites, and inflammatory phenotypes; others, with non-inflammatory states or markers of neurodegeneration 
. There have been limited studies of brain tissues from treated patients with HAND to evaluate what biologic pathways remain abnormally regulated under ART, with studies largely focused on single cell types or molecules 
. Comprehensive analysis of the spectrum of molecular abnormalities in the brain that may underlie HAND in the presence of ART has not yet been undertaken.
Here we used functional genomics to conduct comparative analysis of genome-wide gene expression profiles in brain tissues from treated and untreated patients who died with HAND. Functional genomics has been applied with success to identification of complex molecular pathways in carcinogenesis and to better detection, classification, and prognosis of some cancers 
. This approach has also been used extensively to investigate the transcriptome correlates of HIV-1 infection in peripheral tissues from HIV-1-infected patients including lymph nodes 
T cells 
, monocytes 
, B cells 
, and gastrointestinal mucosa 
. Some of these studies determined the effects of ART on HIV-1 transcriptomes in patients, revealing categories of treatment-responsive genes as well as aberrantly expressed transcripts that may serve as targets for future therapies 
. In a related approach, a recent study evaluated gene expression profiles of blood monocytes as a function of ART and neuropsychological impairment of HIV-1-infected patients 
. Interestingly in this case, there was no correlation between changes in blood monocyte transcriptomes under treatment and clinical HAND 
. Generally, this research benefited from the ability to serially sample peripheral tissues and individual cell types in living individuals, allowing ongoing evaluation of treatment.
In contrast, analyses of human brain tissues by functional genomics can only be conducted retrospectively in autopsy tissues and are complicated by the multicellular interactions underlying central nervous system diseases 
. Nonetheless, large-scale, cross-sectional gene expression profiling of brain tissues has revealed potential pathogenic pathways in Alzheimer's disease (AD) 
, Parkinson's disease 
, chronic schizophrenia 
, multiple sclerosis 
, and viral encephalitis 
. With respect to HIV-1 infection in the brain, investigators reported transcriptional changes in selected gene categories such as anion channels in the frontal cortex of patients who died with HAND 
. Another group reported aberrant expression of genes specific to HIV-1 encephalitis (HIVE) 
, established a correlation between use of methamphetamine and up-regulation of interferon genes in these patients 
, and investigated the role of microRNA in gene regulation in HIV-1-infected brain 
. To our knowledge, these studies did not consider the effects of ART on brain gene dysregulation in HAND.
The Manhattan HIV Brain Bank (MHBB; member of the National NeuroAIDS Tissue Consortium) follows a cohort of advanced-stage, HIV-1-infected individuals with a high prevalence of well-characterized cognitive dysfunction; with entry to the study, participants agree to be organ donors upon death. The antiviral treatment status of study participants is monitored while in the program. Thus, brain tissues obtained by this program provide an opportunity to examine the potentially diverse processes underlying HAND in the ART era. We report herein the gene expression profiles of individuals with HAND focusing on the impact of ART on these profiles.