Induction of pathogenic sets of genes in macrophages and neurons in NeuroAIDS.
The etiology of the central nervous system (CNS) alterations after human immunodeficiency virus (HIV) infection, such as dementia and encephalitis, remains unknown. We have used microarray analysis in a monkey model of neuroAIDS to identify 98 genes, many previously unrecognized in lentiviral CNS pathogenesis, whose expression is significantly up-regulated in the frontal lobe of simian immunodeficiency virus-infected brains. Further, through immunohistochemical illumination, distinct classes of genes were found whose protein products localized to infiltrating macrophages, endothelial cells and resident glia, such as CD163, Glut5, and ISG15. In addition we found proteins induced in cortical neurons (ie, cyclin D3, tissue transglutaminase, alpha1-antichymotrypsin, and STAT1), which have not previously been described as participating in simian immunodeficiency virus or HIV-related CNS pathology. This molecular phenotyping in the infected brains revealed pathways promoting entry of macrophages into the brain and their subsequent detrimental effects on neurons. These data support the hypothesis that in HIV-induced CNS disease products of activated macrophages and astrocytes lead to CNS dysfunction by directly damaging neurons, as well as by induction of altered gene and protein expression profiles in neurons themselves which are deleterious to their function.
Roberts
Eleanor S
ES
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA.
Zandonatti
Michelle A
MA
Watry
Debbie D
DD
Madden
Lisa J
LJ
Henriksen
Steven J
SJ
Taffe
Michael A
MA
Fox
Howard S
HS
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002465:Cell Movement; D002493:Central Nervous System Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D003599:Cytoskeleton / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D007107:Immune System / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007372:Interferons / Q000494:pharmacology; D008253:Macaca mulatta; D008264:Macrophages / Q000378:metabolism* / Q000821:virology; D017628:Microglia / Q000378:metabolism / Q000821:virology; D009000:Monocytes / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000821:virology; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics; D012313:RNA / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015302:Simian Immunodeficiency Virus; D014158:Transcription, Genetic
D011506:Proteins; C018589:lysosomal proteins; D012313:RNA; D007372:Interferons