Inhibition of type 1 human immunodeficiency virus replication by a tat antagonist to which the virus remains sensitive after prolonged exposure in vitro.
The transactivator of transcription, Tat, of human immunodeficiency virus type 1 (HIV-1) is required for viral replication. Inhibition of Tat function could have the potential to keep integrated provirus in dormancy. In the presence of Tat, Ro 24-7429, an analog of Ro 5-3335, inhibited expression of indicator genes controlled by the HIV-1 long terminal repeat promoter in transient transfection assays and in a constitutive cell line at noncytotoxic concentrations. Reduction of steady-state mRNA of the indicator gene by the compound correlated with reduction of the gene product in the constitutive cell line. Ro 24-7429 has broad activity against several strains of HIV-1 in different cell lines, peripheral blood lymphocytes, and macrophages (IC90 = 1-3 microM). Importantly, Ro 24-7429 inhibited viral replication in both acute and chronic infection in vitro, a characteristic expected of a Tat antagonist and not shared by viral reverse transcriptase inhibitors. Consistent with this, the compound reduced cell-associated viral RNA and proteins and partially restored cell-surface CD4 in chronically infected cells. After 2 years of continued weekly passage of the virus in fresh CEM cells grown in the presence of the compound at 1 or 10 microM, the virus did not develop resistance to the drug. These results indicate that the compound's action might involve a cellular factor.
Hsu
M C
MC
Department of Virology, Hoffmann-La Roche Inc., Nutley, NJ 07110.
Dhingra
U
U
Earley
J V
JV
Holly
M
M
Keith
D
D
Nalin
C M
CM
Richou
A R
AR
Schutt
A D
AD
Tam
S Y
SY
Potash
M J
MJ
D000469:Alkaline Phosphatase / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001569:Benzodiazepines; D015704:CD4 Antigens / Q000096:biosynthesis; D002478:Cells, Cultured; D015536:Down-Regulation; D004353:Drug Evaluation, Preclinical; D004352:Drug Resistance, Microbial; D015696:Gene Products, tat / Q000037:antagonists & inhibitors*; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008214:Lymphocytes / Q000382:microbiology; D008264:Macrophages / Q000382:microbiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011758:Pyrroles; D012692:Serial Passage; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D014779:Virus Replication / Q000187:drug effects; D054322:tat Gene Products, Human Immunodeficiency Virus
D000998:Antiviral Agents; D015704:CD4 Antigens; D015696:Gene Products, tat; D011758:Pyrroles; D054322:tat Gene Products, Human Immunodeficiency Virus; D001569:Benzodiazepines; C070024:Ro 24-7429; D000469:Alkaline Phosphatase