Significant effects of antiretroviral therapy on global gene expression in brain tissues of patients with HIV-1-associated neurocognitive disorders
- PMID: 21909266
- PMCID: PMC3164642
- DOI: 10.1371/journal.ppat.1002213
Significant effects of antiretroviral therapy on global gene expression in brain tissues of patients with HIV-1-associated neurocognitive disorders
Abstract
Antiretroviral therapy (ART) has reduced morbidity and mortality in HIV-1 infection; however HIV-1-associated neurocognitive disorders (HAND) persist despite treatment. The reasons for the limited efficacy of ART in the brain are unknown. Here we used functional genomics to determine ART effectiveness in the brain and to identify molecular signatures of HAND under ART. We performed genome-wide microarray analysis using Affymetrix U133 Plus 2.0 Arrays, real-time PCR, and immunohistochemistry in brain tissues from seven treated and eight untreated HAND patients and six uninfected controls. We also determined brain virus burdens by real-time PCR. Treated and untreated HAND brains had distinct gene expression profiles with ART transcriptomes clustering with HIV-1-negative controls. The molecular disease profile of untreated HAND showed dysregulated expression of 1470 genes at p<0.05, with activation of antiviral and immune responses and suppression of synaptic transmission and neurogenesis. The overall brain transcriptome changes in these patients were independent of histological manifestation of HIV-1 encephalitis and brain virus burdens. Depending on treatment compliance, brain transcriptomes from patients on ART had 83% to 93% fewer dysregulated genes and significantly lower dysregulation of biological pathways compared to untreated patients, with particular improvement indicated for nervous system functions. However a core of about 100 genes remained similarly dysregulated in both treated and untreated patient brain tissues. These genes participate in adaptive immune responses, and in interferon, cell cycle, and myelin pathways. Fluctuations of cellular gene expression in the brain correlated in Pearson's formula analysis with plasma but not brain virus burden. Our results define for the first time an aberrant genome-wide brain transcriptome of untreated HAND and they suggest that antiretroviral treatment can be broadly effective in reducing pathophysiological changes in the brain associated with HAND. Aberrantly expressed transcripts common to untreated and treated HAND may contribute to neurocognitive changes defying ART.
Conflict of interest statement
The authors have declared that no competing interests exist.
Figures






References
-
- Chang L, Ernst T, Leonido-Yee M, Witt M, Speck O, et al. Highly active antiretroviral therapy reverses brain metabolite abnormalities in mild HIV dementia. Neurology. 1999;53:782–789. - PubMed
-
- Robertson KR, Robertson WT, Ford S, Watson D, Fiscus S, et al. Highly active antiretroviral therapy improves neurocognitive functioning. J Acquir Immune Defic Syndr. 2004;36:562–566. - PubMed
-
- Robertson KR, Smurzynski M, Parsons TD, Wu K, Bosch RJ, et al. The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS. 2007;21:1915–1921. - PubMed
-
- Sacktor N, McDermott MP, Marder K, Schifitto G, Selnes OA, et al. HIV-associated cognitive impairment before and after the advent of combination therapy. J Neurovirol. 2002;8:136–142. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- R21 NS061646/NS/NINDS NIH HHS/United States
- R01DA017618/DA/NIDA NIH HHS/United States
- R24 MH059724/MH/NIMH NIH HHS/United States
- P01 NS031492/NS/NINDS NIH HHS/United States
- R24MH59724/MH/NIMH NIH HHS/United States
- P01NS31492/NS/NINDS NIH HHS/United States
- U01MH083501/MH/NIMH NIH HHS/United States
- R01MH083627/MH/NIMH NIH HHS/United States
- U01 MH083501/MH/NIMH NIH HHS/United States
- U01 MH083545/MH/NIMH NIH HHS/United States
- R01 DA017618/DA/NIDA NIH HHS/United States
- R21NS061646/NS/NINDS NIH HHS/United States
- R01 MH083627/MH/NIMH NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases