HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REVERSE-TRANSCRIPTASE GENOTYPE AND DRUG SUSCEPTIBILITY CHANGES IN INFECTED INDIVIDUALS RECEIVING DIDEOXYINOSINE MONOTHERAPY FOR 1 TO 2 YEARS

The genetic mechanisms of human immunodeficiency virus type 1 (HIV-1) resistance to dideoxyinosine (ddI) in vivo have been described based o n data from primary HIV-1 isolates, To better define the spectrum of H IV-1 reverse transcriptase (RT) changes occurring during ddI therapy, we determined the genotype and ddI susceptibility of the RT gene of HI V RNA isolated from the plasma of 23 patients who had received 1 to 2 years (mean, 87 +/- 16 weeks) of ddI monotherapy, Population-based seq uencing of plasma virus showed that 12 of 23 (52%) patients developed known ddI resistance mutations: L74V (7 patients), K65R (2 patients), L74V with M184V (3 patients), and L74V with K65R (1 patient), Five pat ients developed one or more known zidovudine resistance mutations (at codons 41, 67, 70, 215, and/or 219) during the study, Other amino acid substitutions were found, but only S68G and L210W occurred in more th an one patient, Studies of sensitivity to ddI were performed on popula tion-based recombinant-virus stocks generated by homologous recombinat ion between a plasmid containing an HXB2 clone with the RT gene delete d and RT-PCR products of the RT genes from patients' plasma RNA, The s equences of the virus stocks produced by this procedure were typically identical to the sequence of the input PCR product from plasma RNA, B oth an MT-2 cell-based culture assay and a cell-free virion-associated RT inhibition assay showed that viruses possessing an L74V and/or M18 4V mutation or a K65R mutation had reduced sensitivity to ddI, Viruses without these specific mutations had no change in sensitivity to ddI, The results presented here show that the spectrum of RT mutations in a population of more complex than previously described, The developmen t of multiple mutational patterns, including those that confer resista nce to other nucleoside analogs, highlights the complexity of using th e currently available nucleoside analogs for antiretroviral therapy.