Prevention of the spread of HIV-1 infection with nonnucleoside reverse transcriptase inhibitors

Certain bisheteroarylpiperazines (BHAPs) directly inhibit the replication of human immunodeficiency virus type 1 (HIV-1) and block the spread of infection to susceptible populations of cells. At a 1 microM concentration three analogs, U-87201, U-88204, and U-89674, inhibited the replication of HIV-1 in MT-2 cells by 83, 100, and 93%, respectively. At the same concentration, U-88204 completely inhibited replication of primary HIV-1 isolates in peripheral blood mononuclear cells. Replication of 3'-azido-2',3'-dideoxythymidine (AZT)-resistant strains of HIV-1 was also inhibited by U-88204. When MT-2 cells that were lytically infected with HIV-1 were mixed with uninfected MT-2 cells, U-88204 provided complete protection to the uninfected cells. Integrated proviral DNA sequences were not detected by the polymerase chain reaction technique in this culture after 15 days in the presence of drug. The resultant healthy cell culture was subsequently maintained without drug with no evidence of latent proviral DNA. Serial passage of a laboratory strain and a primary isolate of HIV-1 in cell culture in the presence of increasing concentrations of U-88204 yielded virus populations which were at least 100-fold resistant to the drug. These resistant viruses also showed cross-resistance to the pyridinone class of nonnucleoside inhibitors but were sensitive to AZT. Analysis of the nucleotide sequence of resistant viruses revealed mutations at conserved regions of the reverse transcriptase (RT) gene. The results presented here suggest the therapeutic potential of U-88204 in the combination therapy for HIV-1 infection.