Significant Effects of Antiretroviral Therapy on Global Gene Expression in Brain Tissues of Patients with HIV-1-Associated Neurocognitive Disorders

PLoS Pathogens

Andrew I. Brooks¹  Jacinta Murray²  Susan Morgello²  Seon-Young Kim³  David J. Volsky⁴  Wei Chao⁴  Alejandra Borjabad⁴  Mary Jane Potash⁴ 

[1] Department of Genetics, Environmental and Occupational Health Science Institute (EOHSI), Rutgers University, Piscataway, New Jersey, United States of America;Department of Pathology and Neuroscience, The Mount Sinai Medical Center, New York, New York, United States of America;Human Genomics Laboratory, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea;Molecular Virology Division, St. Luke's-Roosevelt Hospital Center and Columbia University, New York, New York, United States of America

关键词: Gene expression;    HIV-1;    Microarrays;    Antiretroviral therapy;    Transcriptome analysis;    Immune response;    Polymerase chain reaction;    Viral load;   

DOI  :  10.1371/journal.ppat.1002213

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY