CT-2576, an inhibitor of phospholipid signaling, suppresses constitutive and induced expression of human immunodeficiency virus.
Viruses such as human immunodeficiency virus (HIV) require cellular activation for expression. Cellular activation in lymphoid cells is associated with augmented accumulation of certain phosphatidic acid (PA) species derived from the hydrolysis of glycan phosphatidylinositol (GPI). This suggests that activation of a phospholipid pathway may play a role in initiation of viral replication. To test this hypothesis, we examined the effect of tat gene expression on the production of cellular PA species, as the Tat protein is essential for HIV expression and has been implicated in activating the expression of multiple host cellular genes. Expression of tat increased the expression of PA. We then tested whether synthetic inhibitors of PA metabolism would inhibit activation of the HIV long terminal repeat by Tat and tumor necrosis factor alpha (TNF-alpha). CT-2576 suppressed both PA generation induced by Tat and HIV long terminal repeat-directed gene expression in response to Tat or TNF-alpha at a posttranscriptional step. CT-2576 also inhibited constitutive as well as TNF-alpha- and interleukin 6-induced expression of HIV p24 antigen in chronically infected U1 cells and in peripheral blood lymphocytes acutely infected with a clinical isolate of HIV. Pharmacological inhibition of synthesis of selected PA species may therefore provide a therapeutic approach to suppression of HIV replication.
Leung
D W
DW
Cell Therapeutics, Inc., Seattle, WA 98119, USA.
Peterson
P K
PK
Weeks
R
R
Gekker
G
G
Chao
C C
CC
Kaplan
A H
AH
Balantac
N
N
Tompkins
C
C
Underiner
G E
GE
Bursten
S
S
D000469:Alkaline Phosphatase / Q000096:biosynthesis; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D015696:Gene Products, tat / Q000096:biosynthesis; D015756:Genes, tat / Q000187:drug effects; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D006678:HIV / Q000187:drug effects / Q000502:physiology*; D016325:HIV Long Terminal Repeat / Q000187:drug effects*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D007668:Kidney; D007700:Kinetics; D008969:Molecular Sequence Data; D010712:Phosphatidic Acids / Q000378:metabolism; D010743:Phospholipids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*; D014970:Xanthines / Q000494:pharmacology*; D054322:tat Gene Products, Human Immunodeficiency Virus; D000093242:Interleukin-6 Inhibitors
D000469:Alkaline Phosphatase; D000998:Antiviral Agents; D017931:DNA Primers; D015696:Gene Products, tat; D017261:Glycosylphosphatidylinositols; D015850:Interleukin-6; D010712:Phosphatidic Acids; D010743:Phospholipids; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D014970:Xanthines; D054322:tat Gene Products, Human Immunodeficiency Virus; D000093242:Interleukin-6 Inhibitors; C093734:CT 2576