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 immumodeficiency vi rus type 1 (HIV-1) is required for viral replication. Inhibition of Ta t function could have the potential to keep integrated provirus in dor mancy. In the presence of Tat, Ro 24-7429, an analog of Ro 5-3335, inh ibited expression of indicator genes controlled by the HIV-1 long term inal repeat promoter in transient transfection assays and in a constit utive cell line at noncytotoxic concentrations. Reduction of steady-st ate mRNA of the indicator gene by the compound correlated with reducti on of the gene product in the constitutive cell line. Ro 24-7429 has b road activity against several strains of HIV-1 in different cell lines , peripheral blood lymphocytes, and macrophages (IC90 = 1-3 muM. Impor tantly, Ro 24-7429 inhibited viral replication in both acute and chron ic infection in vitro, a characteristic expected of a Tat antagonist a nd not shared by viral reverse transcriptase inhibitors. Consistent wi th this, the compound reduced cell-associated viral RNA and proteins a nd partially restored cell-surface CD4 in chronically infected cells. After 2 years of continued weekly passage of the virus in fresh CEM ce lls grown in the presence of the compound at 1 or 10 muM, the virus di d not develop resistance to the drug. These results indicate that the compound's action might involve a cellular factor.