Effects of human immunodeficiency virus type 1 on astrocyte gene expression and function: potential role in neuropathogenesis.
Neurodegeneration and dementia caused by human immunodeficiency virus type 1 (HIV-1) infection of the brain are common complications of acquired immunodeficiency syndrome (AIDS). Introduction of highly active antiretroviral therapy (HAART) reduced the incidence of HIV-1-associated dementia, but so far had no effect on the high frequency of milder neurological disorders caused by HIV-1. This indicates that some neuropathogenic processes persist during limited HIV-1 replication in the central nervous system (CNS). The authors are evaluating the hypothesis that interaction of HIV-1 with astrocytes, which bind HIV-1 but support limited productive HIV-1 infection, may contribute to these processes by disrupting astrocyte functions that are important for neuronal activity or survival. Using laser-capture microdissection on brain tissue samples from HIV-1-infected individuals, we found that HIV-1 DNA can be detected in up to 1% of cortical and basal ganglia astrocytes, thus confirming HIV-1 infection in astrocytes from symptomatic patients. Using rapid subtraction hybridization, the authors cloned and identified 25 messenger RNAs in primary human fetal astrocytes either up-regulated or down-regulated by native HIV-1 infection or exposure to gp120 in vitro. Extending this approach to gene microarray analysis using Affymetrix U133A/B gene chips, the authors determined that HIV-1 alters globally and significantly the overall program of gene expression in astrocytes, including changes in transcripts coding for cytokines, G-coupled protein receptors, transcription factors, and others. Focusing on a specific astrocyte function relevant to neuropathogenesis, the authors showed that exposure of astrocytes to HIV-1 or gp120 in vitro impairs the ability of the cells to transport L-glutamate and the authors related this defect to transcriptional inhibition of the EAAT2 glutamate transporter gene. These findings define new pathways through which HIV-1 may contribute to neuropathogenesis under conditions of limited virus replication in the brain.
Wang
Zhuying
Z
Molecular Virology Division, St. Luke's-Roosevelt Hospital Center and College of Physicians and Surgeons, Columbia University, New York, New York 10019, USA.
Trillo-Pazos
Gusta
G
Kim
Seon-Young
SY
Canki
Mario
M
Morgello
Susan
S
Sharer
Leroy R
LR
Gelbard
Harris A
HA
Su
Zao-Zhong
ZZ
Kang
Dong-Chul
DC
Brooks
Andrew I
AI
Fisher
Paul B
PB
Volsky
David J
DJ
D015526:AIDS Dementia Complex / Q000209:etiology* / Q000503:physiopathology*; D001253:Astrocytes / Q000502:physiology* / Q000821:virology*; D015497:HIV-1; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis