A MUTATION IN REVERSE-TRANSCRIPTASE OF BIS(HETEROARYL)PIPERAZINE-RESISTANT HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 THAT CONFERS INCREASED SENSITIVITY TO OTHER NONNUCLEOSIDE INHIBITORS

Several nonnucleoside inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) have been described, including Ne virapine, thiobenzimidazolone (TIBO) derivatives, pyridinone derivativ es such as L-697,661, and the bis(heteroaryl)piperazines (BHAPs). HIV- 1 resistant to L-697,661 or Nevirapine emerges rapidly in infected pat ients treated with these drugs, and the resistance is caused primarily by substitutions at amino acids 181 and 103 of RT that also confer cr oss resistance to the other nonnudeoside inhibitors. We describe deriv ation and characterization of two BHAP-resistant HIV-1 variants that d iffer from this pattern of cross resistance. With both variants, HIV-1 resistance to BHAP RT inhibitors was caused by a RT mutation that res ults in a proline-to-leucine substitution at amino acid 236 (P236L). R ather than conferring cross resistance to other RT inhibitors, this su bstitution sensitized RT 7- to 10-fold to Nevirapine, TIBO R82913, and L-697,661 without influencing sensitivity to nucleoside analogue RT i nhibitors. This sensitization caused by P236L was also observed in cel l culture with BHAP-resistant HIV-1. The effects of the P236L RT subst itution suggest that emergence of BHAP-resistant virus in vivo could p roduce a viral population sensitized to inhibition by these other nonn ucleoside RT inhibitors.