Human immunodeficiency virus type 1-induced macrophage gene expression includes the p21 gene, a target for viral regulation.
In contrast to CD4+ T cells, human immunodeficiency virus type 1 (HIV-1)-infected macrophages typically resist cell death, support viral replication, and consequently, may facilitate HIV-1 transmission. To elucidate how the virus commandeers the macrophage's intracellular machinery for its benefit, we analyzed HIV-1-infected human macrophages for virus-induced gene transcription by using multiple parameters, including cDNA expression arrays. HIV-1 infection induced the transcriptional regulation of genes associated with host defense, signal transduction, apoptosis, and the cell cycle, among which the cyclin-dependent kinase inhibitor 1A (CDKN1A/p21) gene was the most prominent. p21 mRNA and protein expression followed a bimodal pattern which was initially evident during the early stages of infection, and maximum levels occurred concomitant with active HIV-1 replication. Mechanistically, viral protein R (Vpr) independently regulates p21 expression, consistent with the reduced viral replication and lack of p21 upregulation by a Vpr-negative virus. Moreover, the treatment of macrophages with p21 antisense oligonucleotides or small interfering RNAs reduced HIV-1 infection. In addition, the synthetic triterpenoid and peroxisome proliferator-activated receptor gamma ligand, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), which is known to influence p21 expression, suppressed viral replication. These data implicate p21 as a pivotal macrophage facilitator of the viral life cycle. Moreover, regulators of p21, such as CDDO, may provide an interventional approach to modulate HIV-1 replication.
Vázquez
Nancy
N
National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA. nvazquez@mail.nih.gov
Greenwell-Wild
Teresa
T
Marinos
Nancy J
NJ
Swaim
William D
WD
Nares
Salvador
S
Ott
David E
DE
Schubert
Ulrich
U
Henklein
Peter
P
Orenstein
Jan M
JM
Sporn
Michael B
MB
Wahl
Sharon M
SM
D019380:Anti-HIV Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015870:Gene Expression; D016336:Gene Products, vpr / Q000235:genetics / Q000502:physiology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008264:Macrophages / Q000378:metabolism* / Q000821:virology*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011506:Proteins / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D014779:Virus Replication / Q000187:drug effects; D054325:vpr Gene Products, Human Immunodeficiency Virus
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D019380:Anti-HIV Agents; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016336:Gene Products, vpr; D016376:Oligonucleotides, Antisense; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054325:vpr Gene Products, Human Immunodeficiency Virus; D009828:Oleanolic Acid