THE SAME MUTATION THAT ENCODES LOW-LEVEL HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 RESISTANCE TO 2',3'-DIDEOXYINOSINE AND 2',3'-DIDEOXYCYTIDINE CONFERS HIGH-LEVEL RESISTANCE TO THE (-) ENANTIOMER OF 2',3'-DIDEOXY-3'-THIACYTIDINE

Variants of human immunodeficiency virus type 1 that display 500- to 1,000-fold resistance to the (-) enantiomer of 2'-deoxy-3'-thiacytidine and almost-equal-to 4- to 8-fold resistance to 2',3'-dideoxycytidine and 2',3'-dideoxyinosine have been generated through in vitro selection with the former compound. The polymerase regions of several of these resistant viruses shared a codon alteration at site 184 (ATG --> GTG; methionine --> valine), a mutation previously associated with low-level resistance to 2',3'-dideoxyinosine and 2',3'-dideoxycytidine. The biological relevance of this mutation for the (-) enantiomer of 2'-deoxy-3'-thiacytidine was confirmed by site-directed mutagenesis with the HXB2-D clone of human immunodeficiency virus type 1.