InPheno AG

Basel, Switzerland

InPheno AG

Basel, Switzerland
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Miazga A.,Polish Academy of Sciences | Hamy F.,InPheno AG | Louvel S.,InPheno AG | Klimkait T.,InPheno AG | And 5 more authors.
Antiviral Research | Year: 2011

Various thiated analogues of thymine 2',3'-dideoxy-3'-fluoronucleoside (FLT) and their 5'-monophosphates and 5'-triphosphates were prepared with the use of modified multistep procedures. The thiated analogues of FLT and FLTMP were evaluated against the wild type and drug- and multidrug-resistant strains of HIV-1, using the replicative phenotyping format of the deCIPhR assay, and showed potent inhibition of drug-resistant HIV-1 strains at low cytotoxicity. Additionally, inhibition of recombinant drug resistant forms of reverse transcriptase from single and multiple HIV-1 mutants by the synthesized 5'-triphosphates was investigated. The strongest inhibition was observed for K103N and Δ67 mutants and the most potent anti-HIV-1 activity against drug resistant strains and the lowest cytotoxicity was exerted by S 4FLTMP and FLTMP which may be regarded as potential anti-HIV/AIDS agents. © 2011 Elsevier B.V.


Kemal K.S.,New York State Department of Health | Kemal K.S.,Yeshiva University | Ramirez C.M.,University of California at Los Angeles | Burger H.,New York State Department of Health | And 16 more authors.
AIDS Research and Human Retroviruses | Year: 2012

Multidrug-resistant (MDR) HIV-1 presents a challenge to the efficacy of antiretroviral therapy (ART). To examine mechanisms leading to MDR variants in infected individuals, we studied recombination between single viral genomes from the genital tract and plasma of a woman initiating ART. We determined HIV-1 RNA sequences and drug resistance profiles of 159 unique viral variants obtained before ART and semiannually for 4 years thereafter. Soon after initiating zidovudine, lamivudine, and nevirapine, resistant variants and intrapatient HIV-1 recombinants were detected in both compartments; the recombinants had inherited genetic material from both genital and plasma-derived viruses. Twenty-three unique recombinants were documented during 4 years of therapy, comprising ∼22% of variants. Most recombinant genomes displayed similar breakpoints and clustered phylogenetically, suggesting evolution from common ancestors. Longitudinal analysis demonstrated that MDR recombinants were common and persistent, demonstrating that recombination, in addition to point mutation, can contribute to the evolution of MDR HIV-1 in viremic individuals. © Copyright 2012, Mary Ann Liebert, Inc.


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.


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.


Edwards S.,University of Basel | Stucki H.,University of Basel | Stucki H.,Hoffmann-La Roche | 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.


Opravil M.,University of Zürich | Klimkait T.,University of Basel | Louvel S.,InPheno AG | Wolf E.,MUC Research | And 6 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2010

Background: The M184V mutation decreases the replication capacity of HIV-1. This prospective study aimed to characterize the virologic and immunologic changes during monotherapy with lamivudine (3TC) in patients with limited options for a fully suppressive new therapy. Methods: Clinically stable patients with CD4 cells greater than 300/μL, previous virologic failure, and a M184V mutation were treated with 3TC 300 mg once daily during 48 weeks. The primary study endpoint was time to CD4 cell decrease by 30% or to below 200 cells/μL. Results: Patients were switched from either a protease inhibitor (PI)-containing highly active antiretroviral therapy (PI group, N = 10) or from reverse transcriptase (RT) inhibitor regimens (RT group, N = 16). Among all 26 patients with a median baseline HIV-1 RNA of 3866 copies/mL and CD4 cell count of 432/μL, the probability of reaching the endpoint after 12, 24, 36, and 48 weeks was 15%, 36%, 57%, and 70%, respectively. The median time to the endpoint was 6.0 months. In the PI versus the RT group, 81% versus 40% reached the CD4 endpoint (P < 0.05); the CD4 decline was-170 versus-99 cells/μL (P < 0.05). The replication capacity of the RT increased from mean 53% to 73% (P < 0.01). The increase in the replication capacity of the protease was greater in the PI group (from 51% to 72%, P = 0.07) than in the RT group (from 70% to 82%, P = 0.32). Mutations detected at baseline reverted partially to the wild type. No new HIV-associated illnesses and no 3TC-related toxicities were reported during the study. Conclusions: 3TC monotherapy as a partial treatment interruption did not prevent immunologic deterioration in the majority of patients. It may be considered a temporary maintenance strategy in selected patients failing under RT inhibitors only. Withdrawal of the residual activity of a PI from the failing regimen led to a faster CD4 decline, possibly because of greater increase in the fitness of the protease gene. © 2010 by Lippincott Williams & Wilkins.


PubMed | University of Basel, University of Cologne and InPheno AG
Type: Evaluation Studies | Journal: Journal of clinical microbiology | Year: 2015

Key clinical studies for HIV coreceptor antagonists have used the phenotyping-based Trofile test. Meanwhile various simpler-to-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.


Louvel S.,InPheno AG | Louvel S.,University of Basel | Moodley N.,Council for Scientific and Industrial Research | Seibert I.,University of Basel | And 7 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.


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.

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