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Rapid Screening of HIV Reverse Transcriptase and Integrase Inhibitors
Published on: April 9, 2014
ATP-dependent removal of nucleoside reverse transcriptase inhibitors by human immunodeficiency virus type 1 reverse
Lisa K Naeger1, Nicolas A Margot, Michael D Miller
1Gilead Sciences, Inc., Foster City, California 94404, USA.
Antimicrobial Agents and Chemotherapy
|June 19, 2002
Summary
Human immunodeficiency virus (HIV) resistance involves ATP-dependent removal of nucleoside reverse transcriptase inhibitors by HIV-1 RT. Thymidine analogs like zidovudine (AZT) and stavudine (d4T) are most efficiently removed, contributing to drug resistance.
Area of Science:
- Virology
- Biochemistry
- Drug Resistance Mechanisms
Background:
- Nucleoside reverse transcriptase inhibitors (NRTIs) are key in HIV treatment.
- HIV-1 reverse transcriptase (RT) mutations can confer resistance to NRTIs.
- ATP-dependent removal of NRTIs by HIV-1 RT is a proposed resistance mechanism.
Purpose of the Study:
- To investigate the ATP-dependent removal of NRTIs by HIV-1 RT with thymidine analog resistance mutations.
- To determine the relative rates of removal for eight different NRTIs.
- To assess the impact of complementary deoxynucleoside triphosphates on NRTI removal.
Main Methods:
- Recombinant wild-type and mutant HIV-1 RT enzymes were utilized.
- Enzymes were analyzed for their ability to remove eight NRTIs in the presence of ATP.
- Rates of inhibitor removal were quantified and compared.
Main Results:
- Mutant HIV-1 RT showed significant ATP-dependent removal of zidovudine (AZT) and stavudine (d4T).
- The order of removal efficiency was AZT > d4T >> others, with tenofovir showing minimal removal.
- Complementary deoxynucleoside triphosphates reduced removal of some NRTIs but not AZT or abacavir.
Conclusions:
- ATP-dependent removal of AZT and d4T by mutant HIV-1 RT contributes to thymidine analog resistance.
- The varying removal efficiencies explain differential resistance patterns observed in patients.
- Findings provide insight into NRTI resistance mechanisms and potential therapeutic strategies.
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