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Märstetten-Dorf, Switzerland

Omolo J.J.,University of Witwatersrand | Omolo J.J.,Council for Scientific and Industrial Research | Omolo J.J.,University of Dar es Salaam | Maharaj V.,Council for Scientific and Industrial Research | And 7 more authors.
Journal of Natural Products | Year: 2012

Two new anti-HIV xanthones, 6,7,11-trihydroxy-10-methoxy-9-(7-methoxy-3- methyl-1-oxoisochroman-5-yl)-2-methyl-12-oxo-12H-benzo[b]xanthene-4-carboxylic acid (1) and 6,7-dihydroxy-10,11-dimethoxy-9-(7-methoxy-3-methyl-1- oxoisochroman-5-yl)-2-methyl-12-oxo-12H-benzo[b]xanthene-4-carboxylic acid (2), and a new hexadecahydrochrysen-3-ol (3) were isolated from the tubers of Pyrenacantha kaurabassana. Compounds 1 and 2 showed moderate anti-HIV activity when tested in the deCIPhR assay on HIV virus type NL4-3, with IC50 values of 21 and 2 μg/mL, respectively. © 2012 The American Chemical Society and American Society of Pharmacognosy. Source

Edwards S.,University of Basel | Stucki H.,University of Basel | Stucki H.,Roche Holding AG | Bader J.,University of Basel | And 4 more authors.
Journal of Clinical Microbiology | Year: 2015

Key clinical studies for HIV coreceptor antagonists have used the phenotyping-based Trofile test. Meanwhile various simplerto-do genotypic tests have become available that are compatible with standard laboratory equipment and Web-based interpretation tools. However, these systems typically analyze only the most prominent virus sequence in a specimen. We present a new diagnostic HIV tropism test not needing DNA sequencing. The system, XTrack, uses physical properties of DNA duplexes after hybridization of single-stranded HIV-1 env V3 loop probes to the clinical specimen. Resulting "heteroduplexes" possess unique properties driven by sequence relatedness to the reference and resulting in a discrete electrophoretic mobility. A detailed optimization process identified diagnostic probe candidates relating best to a large number of HIV-1 sequences with known tropism. From over 500 V3 sequences representing all main HIV-1 subtypes (Los Alamos database), we obtained a small set of probes to determine the tropism in clinical samples. We found a high concordance with the commercial TrofileES test (84.9%) and the Web-based tool Geno2Pheno (83.0%). Moreover, the new system reveals mixed virus populations, and it was successful on specimens with low virus loads or on provirus from leukocytes. A replicative phenotyping system was used for validation. Our data show that the XTrack test is favorably suitable for routine diagnostics. It detects and dissects mixed virus populations and viral minorities; samples with viral loads (VL) of < 200 copies/ml are successfully analyzed. We further expect that the principles of the platform can be adapted also to other sequence-divergent pathogens, such as hepatitis B and C viruses. © 2015, American Society for Microbiology. All Rights Reserved. Source

Fehr J.,University of Basel | Glass T.R.,University of Basel | Louvel S.,InPheno AG | Louvel S.,University of Basel | And 16 more authors.
Journal of Translational Medicine | Year: 2011

Background: Replicative phenotypic HIV resistance testing (rPRT) uses recombinant infectious virus to measure viral replication in the presence of antiretroviral drugs. Due to its high sensitivity of detection of viral minorities and its dissecting power for complex viral resistance patterns and mixed virus populations rPRT might help to improve HIV resistance diagnostics, particularly for patients with multiple drug failures. The aim was to investigate whether the addition of rPRT to genotypic resistance testing (GRT) compared to GRT alone is beneficial for obtaining a virological response in heavily pre-treated HIV-infected patients.Methods: Patients with resistance tests between 2002 and 2006 were followed within the Swiss HIV Cohort Study (SHCS). We assessed patients' virological success after their antiretroviral therapy was switched following resistance testing. Multilevel logistic regression models with SHCS centre as a random effect were used to investigate the association between the type of resistance test and virological response (HIV-1 RNA <50 copies/mL or ≥1.5log reduction).Results: Of 1158 individuals with resistance tests 221 with GRT+rPRT and 937 with GRT were eligible for analysis. Overall virological response rates were 85.1% for GRT+rPRT and 81.4% for GRT. In the subgroup of patients with >2 previous failures, the odds ratio (OR) for virological response of GRT+rPRT compared to GRT was 1.45 (95% CI 1.00-2.09). Multivariate analyses indicate a significant improvement with GRT+rPRT compared to GRT alone (OR 1.68, 95% CI 1.31-2.15).Conclusions: In heavily pre-treated patients rPRT-based resistance information adds benefit, contributing to a higher rate of treatment success. © 2011 Fehr et al; licensee BioMed Central Ltd. Source

Vidal V.,InPheno AG | Potterat O.,University of Basel | Louvel S.,InPheno AG | Hamy F.,Fisher Bioservices | And 6 more authors.
Journal of Natural Products | Year: 2012

Despite the existence of an extended armamentarium of effective synthetic drugs to treat HIV, there is a continuing need for new potent and affordable drugs. Given the successful history of natural product based drug discovery, a library of close to one thousand plant and fungal extracts was screened for antiretroviral activity. A dichloromethane extract of the aerial parts of Daphne gnidium exhibited strong antiretroviral activity and absence of cytotoxicity. With the aid of HPLC-based activity profiling, the antiviral activity could be tracked to four daphnane derivatives, namely, daphnetoxin (1), gnidicin (2), gniditrin (3), and excoecariatoxin (4). Detailed anti-HIV profiling revealed that the pure compounds were active against multidrug-resistant viruses irrespective of their cellular tropism. Mode of action studies that narrowed the site of activity to viral entry events suggested a direct interference with the expression of the two main HIV co-receptors, CCR5 and CXCR4, at the cell surface by daphnetoxin (1). © 2011 The American Chemical Society and American Society of Pharmacognosy. Source

Louvel S.,InPheno AG | Louvel S.,University of Basel | Moodley N.,Council for Scientific and Industrial Research | Seibert I.,University of Basel | And 6 more authors.
South African Journal of Botany | Year: 2013

As Alepidea amatymbica is commonly used and accepted as medicinal plant in South Africa for various indications, the scientific basis of its anecdotally described, putative anti-HIV properties was investigated. To this aim, we used an accelerated extraction-purification approach; extracts and therein sub-fractions of A. amatymbica were assessed in a cell-based assay targeting the replication of prototypic CXCR4-tropic (NL4-3) or CCR5-tropic (NL-AD87) HIV-1 strains.Sub-fractions of the extracts were generated through semi-preparative high performance liquid chromatography (HPLC) fractionation into triplicates of 96-well microtitre plates; they were then separately subjected to biological analysis and ultra performance liquid chromatography (UPLC) time-of-flight (TOF) analysis. A correlation plot was generated between the biological and chemical data to identify the biologically active compounds in those fractions that showed significant selective anti-HIV activity. The results indicated that rosmarinic acid was present in the wells that showed promising anti-HIV activity in vitro indicating that this compound is at least in part responsible for the antiviral properties of the A. amatymbica extracts. However, compared to standard retroviral inhibitor the anti-HIV activity of the pure compound was found to be only quite moderate. Nevertheless, the accelerated approach described herein increases the efficiency of screens towards identifying drug candidates much earlier in the discovery stage. © 2013 South African Association of Botanists. Source

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