COMPARITIVE ANTI-HIV EVALUATION OF DIVERSE HIV-1-SPECIFIC REVERSE-TRANSCRIPTASE INHIBITOR-RESISTANT VIRUS ISOLATES DEMONSTRATES THE EXISTENCE OF DISTINCT PHENOTYPIC SUBGROUPS

We have biologically and biochemically evaluated a structurally divers e group of HIV-l-specific reverse transcriptase (RT) inhibitors and de termined that the members of this class share many common properties. These include reproducible and selective antiviral activity against a panel of biologically distinct laboratory and clinical strains of HIV- 1, activity against HIV-1 in a wide variety of cultured and fresh huma n cells, and potent inhibition of HIV-1 RT when evaluated using a hete ropolymeric ribosomal RNA template assay. Each of the HIV-l-specific c ompounds was capable of inhibiting HIV replication when challenged at high m.o.i., further distinguishing them from the nucleoside analogs 3 '-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC). When tested in combination with AZT, each of the HIV-l-specific compounds s ynergistically inhibited the replication of HIV-1. HIV-1 isolates resi stant to different HIV-l-specific inhibitors exhibited heterogeneous p atterns of cross-resistance to other members of this pharmaco-logic cl ass. Four distinct phenotypic classes have been defined through the us e of drug-resistant virus isolates which derive from distinct mutation s in the RT. These results indicate that the various subgroups of HIV- 1-specific inhibitors interact differently with HIV-1 RT, suggesting i mportant potential implications for drug combination therapeutic strat egies.