Inhibition of type 1 human immunodeficiency virus replication by a tat antagonist to which the virus remains sensitive after prolonged exposure in vitro.

Abstract

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.

• Authors: M C Hsu, U Dhingra, J V Earley, M Holly, D Keith, C M Nalin, A R Richou, A D Schutt, S Y Tam, M J Potash
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 90 Issue 14 Pg. 6395-9 (Jul 15 1993) ISSN: 0027-8424 [Print] United States
• PMID: 8341644 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antiviral Agents
• CD4 Antigens
• Gene Products, tat
• Pyrroles
• tat Gene Products, Human Immunodeficiency Virus
• Benzodiazepines
• Ro 24-7429
• Alkaline Phosphatase

Topics

• Alkaline Phosphatase (genetics)
• Animals
• Antiviral Agents (pharmacology)
• Benzodiazepines
• CD4 Antigens (biosynthesis)
• Cells, Cultured
• Down-Regulation
• Drug Evaluation, Preclinical
• Drug Resistance, Microbial
• Gene Products, tat (antagonists & inhibitors)
• HIV Long Terminal Repeat (genetics)
• HIV-1 (drug effects)
• Humans
• Lymphocytes (microbiology)
• Macrophages (microbiology)
• Promoter Regions, Genetic (genetics)
• Pyrroles
• Serial Passage
• Transcription, Genetic
• Transfection
• Up-Regulation
• Virus Replication (drug effects)
• tat Gene Products, Human Immunodeficiency Virus