Abstract | BACKGROUND:
Tenofovir disoproxil fumarate (TDF), emtricitabine ( FTC), and efavirenz (EFV) are the three components of the once-daily, single tablet regimen ( Atripla) for treatment of HIV-1 infection. Previous cell culture studies have demonstrated that the double combination of tenofovir (TFV), the parent drug of TDF, and FTC were additive to synergistic in their anti-HIV activity, which correlated with increased levels of intracellular phosphorylation of both compounds. RESULTS: In this study, we demonstrated the combinations of TFV+FTC, TFV+EFV, FTC+EFV, and TFV+ FTC+EFV synergistically inhibit HIV replication in cell culture and synergistically inhibit HIV-1 reverse transcriptase (RT) catalyzed DNA synthesis in biochemical assays. Several different methods were applied to define synergy including median-effect analysis, MacSynergyII and quantitative isobologram analysis. We demonstrated that the enhanced formation of dead-end complexes (DEC) by HIV-1 RT and TFV-terminated DNA in the presence of FTC- triphosphate (TP) could contribute to the synergy observed for the combination of TFV+FTC, possibly through reduced terminal NRTI excision. Furthermore, we showed that EFV facilitated efficient formation of stable, DEC-like complexes by TFV- or FTC-monophosphate (MP)-terminated DNA and this can contribute to the synergistic inhibition of HIV-1 RT by TFV- diphosphate (DP)+EFV and FTC-TP+EFV combinations. CONCLUSION: This study demonstrated a clear correlation between the synergistic antiviral activities of TFV+FTC, TFV+EFV, FTC+EFV, and TFV+ FTC+EFV combinations and synergistic HIV-1 RT inhibition at the enzymatic level. We propose the molecular mechanisms for the TFV+ FTC+EFV synergy to be a combination of increased levels of the active metabolites TFV-DP and FTC-TP and enhanced DEC formation by a chain-terminated DNA and HIV-1 RT in the presence of the second and the third drug in the combination. This study furthers the understanding of the longstanding observations of synergistic anti-HIV-1 effects of many NRTI+NNRTI and certain NRTI+NRTI combinations in cell culture, and provides biochemical evidence that combinations of anti-HIV agents can increase the intracellular drug efficacy, without increasing the extracellular drug concentrations.
|
Authors | Joy Y Feng, John K Ly, Florence Myrick, Derrick Goodman, Kirsten L White, Evguenia S Svarovskaia, Katyna Borroto-Esoda, Michael D Miller |
Journal | Retrovirology
(Retrovirology)
Vol. 6
Pg. 44
(May 13 2009)
ISSN: 1742-4690 [Electronic] England |
PMID | 19439089
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Alkynes
- Anti-HIV Agents
- Benzoxazines
- Cyclopropanes
- DNA, Viral
- Organophosphonates
- Deoxycytidine
- Tenofovir
- reverse transcriptase, Human immunodeficiency virus 1
- HIV Reverse Transcriptase
- Emtricitabine
- Adenine
- efavirenz
|
Topics |
- Adenine
(analogs & derivatives, pharmacology)
- Alkynes
- Anti-HIV Agents
(pharmacology)
- Benzoxazines
(pharmacology)
- Cell Line
- Cyclopropanes
- DNA, Viral
(biosynthesis)
- Deoxycytidine
(analogs & derivatives, pharmacology)
- Drug Synergism
- Emtricitabine
- HIV Reverse Transcriptase
(antagonists & inhibitors)
- HIV-1
(drug effects)
- Humans
- Organophosphonates
(pharmacology)
- Tenofovir
- Virus Replication
(drug effects)
|