Microarray analysis of changes in cellular gene expression induced by productive infection of primary human astrocytes: implications for HAD.
The role of astrocytes in HIV-1 associated dementia (HAD) is not well understood. HIV-1 binds efficiently to astrocytes but infects only a small fraction of the cells in vitro and in vivo. To gain insight into the biology of HIV-1-expressing astrocytes, we productively infected human fetal astrocytes with pseudotyped HIV-1 and employed Affymetrix oligonucleotide microarrays to determine global changes in cellular gene expression at the peak of virus production. With a twofold change as a cutoff, HIV-1 increased transcription of 266 genes in astrocytes and suppressed expression of 468. The functions of highly expressed genes included interferon-mediated antiviral responses (OAS1, IFIT1), intercellular contacts (SH3, glia-derived nexin), cell homing/adhesion (matrix metalloproteinases), and cell-cell signaling (neuropilin 1 and 2). Surprisingly, genes involved in innate immune responses of astrocytes were largely unaffected. The single most significant effect of HIV-1, however, was down-modulation of at least 55 genes involved in control of cell cycle, DNA replication, and cell proliferation, which were overrepresented in these categories with probability scores of 10(-10)-10(-26). Our data suggest that HIV-1 expression in astrocytes profoundly alters host cell biology, with potential consequences for the physiological function of astrocytes during HIV-1 infection in the brain.
Kim
Seon-Young
SY
Molecular Virology Division, St. Luke's-Roosevelt Hospital Center, 432 West 58th Street, Antenucci Building, Room 709, New York, NY 10019, USA.
Li
Jinliang
J
Bentsman
Galina
G
Brooks
Andrew I
AI
Volsky
David J
DJ
D001253:Astrocytes / Q000378:metabolism* / Q000821:virology*; D001921:Brain / Q000166:cytology*; D002452:Cell Count; D002478:Cells, Cultured / Q000378:metabolism / Q000821:virology; D005333:Fetus; D015870:Gene Expression; D020869:Gene Expression Profiling; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000378:metabolism; D018816:Genes, cdc; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D016655:HIV Core Protein p24 / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D005904:Glial Fibrillary Acidic Protein; D016655:HIV Core Protein p24; D012333:RNA, Messenger; D054322:tat Gene Products, Human Immunodeficiency Virus; D049452:Green Fluorescent Proteins