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Why do HIV-1 and HIV-2 use different pathways to develop AZT resistance?
Paul L Boyer1, Stefan G Sarafianos, Patrick K Clark
1HIV Drug Resistance Program, NCI-Frederick, Maryland, USA.
Plos Pathogens
|February 18, 2006
Summary
Human immunodeficiency virus type 1 (HIV-1) resistance to AZT involves ATP-mediated excision. HIV-2 resistance involves reduced AZTTP incorporation, differing from HIV-1 mechanisms.
Area of Science:
- Virology
- Drug Resistance Mechanisms
- Molecular Biology
Background:
- Human immunodeficiency virus (HIV) develops resistance to antiretroviral drugs, including nucleoside analog reverse transcriptase inhibitors (NRTIs) like AZT.
- HIV-1 resistance to AZT commonly involves ATP-mediated excision of AZT monophosphate (AZTMP).
- HIV-2 exhibits AZT resistance primarily through reduced incorporation of AZT triphosphate (AZTTP).
Purpose of the Study:
- To compare the in vitro properties of HIV-1 and HIV-2 reverse transcriptase (RT) concerning AZT resistance mechanisms.
- To elucidate the molecular basis for differential resistance pathways between HIV-1 and HIV-2.
Main Methods:
- In vitro biochemical assays comparing HIV-1 and HIV-2 RT activities.
- Analysis of AZTTP incorporation and AZTMP excision efficiencies.
- Comparison of enzyme kinetics and active site properties.
Main Results:
- HIV-1 RT incorporates AZTTP more readily and is more susceptible to AZTTP inhibition than HIV-2 RT.
- HIV-1 RT is significantly more efficient at ATP-mediated excision of AZTMP compared to HIV-2 RT.
- Differences in the polymerase active site and putative ATP binding sites contribute to these functional disparities.
Conclusions:
- HIV-1 and HIV-2 RT employ distinct primary mechanisms for AZT resistance.
- HIV-1 resistance favors enhancing ATP-mediated excision, while HIV-2 resistance favors excluding AZTTP.
- These distinct pathways reflect evolutionary adaptations suited to each virus type.