IN-VITRO SELECTION FOR DIFFERENT MUTATIONAL PATTERNS IN THE HIV-1 REVERSE-TRANSCRIPTASE USING HIGH AND LOW SELECTIVE PRESSURE OF THE NONNUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITOR HBY-097

In vitro resistance of HIV-1 against high levels of HBY 097 opropoxyca rbonyl-6-methoxy-3-(methylthiomethyl)-3, 4-dihydro-quinoxaline-2(1H)-t hione) and other quinoxaline nonnucleoside reverse transcriptase inhib itors (NNRTIs) is characterized by a specific amino acid substitution in the reverse transcriptase (RT), Gly190Glu. This change results in d ecreased RT polymerase activity and in reduced growth properties of th e corresponding viral variant. Here we show that the appearance of the crippling mutation at codon 190 can be prevented by lowering the sele ctive pressure exerted by HBY 097. Under low selective pressure an acc umulation of other NNRTI-specific mutations is observed. Up to five NN RTI-specific substitutions were detected in some of these virus lineag es. In addition, we report novel RT amino acid changes which were not observed previously, including Val106lle, Val106Leu, and Gly190Thr. HB Y 097 selects for different mutational patterns under high and low sel ective pressure conditions, respectively. Thus, the type of mutations which appear in HIV-infected patients undergoing therapy may be determ ined by the levels of the selecting drug. (C) 1997 Academic Press.