Wild-type and YMDD mutant murine leukemia virus reverse transcriptases areresistant to 2 ',3 '-dideoxy-3 '-thiacytidine

The antiretroviral nucleoside analog 2',3'-dideoxy-3'-thiacytidine (3TC) is a potent inhibitor of wild-type human immunodeficiency virus type 1 (HIV-1 ) reverse transcriptase (RT), A methionine-to-valine or methionine-to-isole ucine substitution at residue 184 in the HIV-1 YMDD motif, which is located at the RT active site, leads to a high level of resistance to 3TC. We soug ht to determine whether 3TC can inhibit the replication of wild-type murine leukemia virus (MLV), which contains V223 at the YVDD active site motif of the MLV RT, and of the V223M, V223I, V223A, and V223S mutant RTs. Surprisi ngly, the wild type and all four of the V223 mutants of MLV RT were highly resistant to 3TC. These results indicate that determinants outside the YVDD motif of MLV RT confer a high level of resistance to 3TC. Therefore, struc tural differences among similar RTs might result in widely divergent sensit ivities to antiretroviral nucleoside analogs.