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Wild-type and YMDD mutant murine leukemia virus reverse transcriptases are resistant to 2',3'-dideoxy-3'-thiacytidine
E K Halvas1, E S Svarovskaia, E O Freed
1Mary Babb Randolph Cancer Center and Department of Biochemistry, West Virginia University, Morgantown, West Virginia 26506, USA.
Journal of Virology
|June 23, 2000
Summary
Murine leukemia virus (MLV) showed high resistance to the antiretroviral drug 3TC, unlike HIV-1. Resistance determinants outside the MLV reverse transcriptase active site suggest varied drug sensitivities among similar viruses.
Area of Science:
- Virology
- Drug Discovery
- Molecular Biology
Background:
- 2',3'-dideoxy-3'-thiacytidine (3TC) is a nucleoside analog effective against wild-type human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT).
- Specific mutations (M184V/I) in the HIV-1 RT YMDD motif confer high-level 3TC resistance.
- Murine leukemia virus (MLV) possesses a YVDD motif in its RT, differing from HIV-1's YMDD.
Purpose of the Study:
- To investigate the susceptibility of wild-type and mutant MLV RT to 3TC.
- To determine if MLV RT, with its YVDD motif, is inhibited by 3TC.
- To explore resistance mechanisms in MLV RT compared to HIV-1 RT.
Main Methods:
- Antiretroviral drug susceptibility assays were performed.
- Wild-type MLV RT and MLV RT mutants (V223M, V223I, V223A, V223S) were analyzed.
- Viral replication inhibition by 3TC was assessed.
Main Results:
- Wild-type MLV RT exhibited high resistance to 3TC.
- All tested MLV RT mutants (V223M, V223I, V223A, V223S) also showed high resistance to 3TC.
- These findings indicate resistance is not solely dependent on the YVDD motif.
Conclusions:
- MLV RT possesses intrinsic high-level resistance to 3TC, independent of the YVDD motif.
- Resistance determinants in MLV RT lie outside the active site motif.
- Structural variations in RTs can lead to significant differences in antiretroviral drug sensitivity.
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