The triple combination of tenofovir, emtricitabine and efavirenz shows synergistic anti-HIV-1 activity in vitro: a mechanism of action study

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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, MacSynergy^®II 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.</p> <p>Conclusion</p> <p>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.</p

Microbial diversity in bushmeat samples recovered from the Serengeti ecosystem in Tanzania

Research Article published by Scientific ReportsBushmeat, the meat and organs derived from wildlife species, is a common source of animal protein in the diets of those living in sub-Saharan Africa and is frequently associated with zoonotic spillover of dangerous pathogens. Given the frequent consumption of bushmeat in this region and the lack of knowledge about the microbial communities associated with this meat, the microbiome of 56 fresh and processed bushmeat samples ascertained from three districts in the Western Serengeti ecosystem in Tanzania was characterized using 16S rRNA metagenomic sequencing. The results show that the most abundant phyla present in bushmeat samples include Firmicutes (67.8%), Proteobacteria (18.4%), Cyanobacteria (8.9%), and Bacteroidetes (3.1%). Regardless of wildlife species, sample condition, season, or region, the microbiome is diverse across all samples, with no significant difference in alpha or beta diversity. The findings also suggest the presence of DNA signatures of potentially dangerous zoonotic pathogens, including those from the genus Bacillus, Brucella, Coxiella, and others, in bushmeat. Together, this investigation provides a better understanding of the microbiome associated with this major food source in samples collected from the Western Serengeti in Tanzania and highlights a need for future investigations on the potential health risks associated with the harvesting, trade, and consumption of bushmeat in Sub-Saharan Afric

Changes in the interfacial tension of chlorinated solvents following flow through UK soils and shallow aquifer material

The interfacial tension (IFT) that arises at the interface between water and an immiscible organic liquid is a key parameter affecting the transport and subsequent fate of the organic liquid in water-saturated porous media. In this paper, data are presented that show how contact between a range of soil types and chlorinated hydrocarbon solvent (CHS) dense nonaqueous phase liquids (DNAPLs) can affect DNAPL/water IFT values. The soils examined are indicative of U.K. soil types and shallow aquifer materials. The solvents investigated were tetrachloroethylene (PCE) and trichloroethylene (TCE). Lab grade, recovered field DNAPL and industrial waste chlorinated solvent mixtures were used. The data from batch and column experiments invariably revealed that water/DNAPL IFT values change following contact with unsaturated soils. In the majority of cases, the IFT values increase following soil exposure. However, after contact with an organic-rich soil, the I FT of the lab grade solvents decreased. The experimental evidence suggests that these reductions are linked to the removal of organic material from the soil and its subsequent incorporation into the solvent. IFT increases in the case of lab solvents are shown to be linked to the removal of stabilizers (added by the manufacturers to obviate degradation) that are removed by adsorption to soil mineral surfaces. Similarly, it is conjectured that adsorption of surface-active compounds from the industrial waste samples to soil surfaces is responsible for increases in the IFT in these samples. Finally, it was observed that invading CHSs are capable of dissolving and subsequently mobilizing in-situ soil contaminants. GC/MS analysis revealed these mobilized soil contaminants to be polyaromatic hydrocarbons and phthalate esters