Resistance mutations selected in vivo under therapy with anti-HIV drug HBY 097 differ from resistance pattern selected in vitro

1999 ◽  
Vol 42 (1) ◽  
pp. 15-24 ◽  
Author(s):  
H RUBSAMENWAIGMANN ◽  
E HUGUENEL ◽  
A SHAH ◽  
A PAESSENS ◽  
H RUOFF ◽  
...  
Keyword(s):  
Resistance Pattern ◽  
Resistance Mutations ◽  
Anti Hiv

scholarly journals Prevalence of doravirine-associated resistance mutations in HIV-1-infected antiretroviral-experienced patients from two large databases in France and Italy

2020 ◽  
Vol 75 (4) ◽  
pp. 1026-1030 ◽  
Author(s):  
Cathia Soulie ◽  
Maria Mercedes Santoro ◽  
Alexandre Storto ◽  
Basma Abdi ◽  
Charlotte Charpentier ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Resistance Mutation ◽  
Resistance Pattern ◽  
Resistance Mutations ◽  
Large Databases ◽  
The Common ◽  
Hiv 1

Abstract Objectives Doravirine, a novel NNRTI, selects for specific mutations in vitro, including mutations at reverse transcriptase (RT) positions 106, 108, 188, 227, 230 and 234. The aim of this study was to examine the prevalence of doravirine-associated resistance mutations in HIV-1-infected antiretroviral-experienced patients. Methods Doravirine-associated resistance mutations identified in vitro or in vivo were studied in a set of 9199 HIV-1 RT sequences from HIV-1 antiretroviral-experienced patients, including 381 NNRTI-failing patients in France and Italy between 2012 and 2017. The following mutations were considered as resistance mutations: V106A/M, V108I, Y188L, G190S, F227C/L/V, M230I/L, L234I, P236L, K103N + Y181C, K103N + P225H and K103N + L100I. Results The frequencies of doravirine-associated resistance mutations (total dataset versus NNRTI-failing patients) were: V106A/M, 0.8% versus 2.6%; V108I, 3.3% versus 9.2%; Y188L, 1.2% versus 2.6%; G190S, 0.3% versus 2.1%; F227C/L/V, 0.5% versus 1.8%; M230I/L, 2.8% versus 0%; L234I, 0.1% versus 0.5%; K103N + Y181C, 3.9% versus 3.9%; K103N + P225H, 2.9% versus 4.7%; and K103N + L100I, 1.7% versus 3.9%, with a significantly higher proportion of these mutations in the NNRTI-failing group (P < 0.05), except for M230I/L and K103N + Y181C. The overall prevalence of sequences with at least one doravirine-associated resistance mutation was 12.2% and 34.9% in the total dataset and NNRTI-failing patients (P < 0.001), respectively. In comparison, the prevalence of the common NNRTI mutations V90I, K101E/P, K103N/S, E138A/G/K/Q/R/S, Y181C/I/V and G190A/E/S/Q were higher (8.9%, 7.9%, 28.6%, 12.6%, 14.2% and 8.9%, respectively). Conclusions These results suggest that doravirine resistance in antiretroviral-experienced patients generally and specifically among NNRTI-failing patients is lower than resistance to other NNRTIs currently used, confirming its distinguishing resistance pattern.

scholarly journals Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hayato Mizuta ◽  
Koutaroh Okada ◽  
Mitsugu Araki ◽  
Jun Adachi ◽  
Ai Takemoto ◽  
...  
Keyword(s):  
Gene Rearrangement ◽  
Kinase Inhibitors ◽  
Inhibitory Effect ◽  
In Vivo Model ◽  
Resistance Mutations ◽  
Lung Cancer Patients ◽  
Short Period ◽  
Tki Resistance

AbstractALK gene rearrangement was observed in 3%–5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI–resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.

scholarly journals Biological Cost of Single and Multiple Norfloxacin Resistance Mutations in Escherichia coli Implicated in Urinary Tract Infections

2005 ◽  
Vol 49 (6) ◽  
pp. 2343-2351 ◽  
Author(s):  
Patricia Komp Lindgren ◽  
Linda L. Marcusson ◽  
Dorthe Sandvang ◽  
Niels Frimodt-Møller ◽  
Diarmaid Hughes
Keyword(s):  
Escherichia Coli ◽  
Urinary Tract ◽  
Infection Model ◽  
Resistance Mutations ◽  
Topoisomerase Iv ◽  
E Coli ◽  
Tract Infections ◽  
Subsequent Selection

ABSTRACT Resistance to fluoroquinolones in urinary tract infection (UTIs) caused by Escherichia coli is associated with multiple mutations, typically those that alter DNA gyrase and DNA topoisomerase IV and those that regulate AcrAB-TolC-mediated efflux. We asked whether a fitness cost is associated with the accumulation of these multiple mutations. Mutants of the susceptible E. coli UTI isolate Nu14 were selected through three to five successive steps with norfloxacin. Each selection was performed with the MIC of the selected strain. After each selection the MIC was measured; and the regions of gyrA, gyrB, parC, and parE, previously associated with resistance mutations, and all of marOR and acrR were sequenced. The first selection step yielded mutations in gyrA, gyrB, and marOR. Subsequent selection steps yielded mutations in gyrA, parE, and marOR but not in gyrB, parC, or acrR. Resistance-associated mutations were identified in almost all isolates after selection steps 1 and 2 but in less than 50% of isolates after subsequent selection steps. Selected strains were competed in vitro, in urine, and in a mouse UTI infection model against the starting strain, Nu14. First-step mutations were not associated with significant fitness costs. However, the accumulation of three or more resistance-associated mutations was usually associated with a large reduction in biological fitness, both in vitro and in vivo. Interestingly, in some lineages a partial restoration of fitness was associated with the accumulation of additional mutations in late selection steps. We suggest that the relative biological costs of multiple mutations may influence the evolution of E. coli strains that develop resistance to fluoroquinolones.

scholarly journals In Vitro and In Silico Antioxidant, Anti-Diabetic, Anti-HIV and Anti-Alzheimer Activity of Endophytic Fungi, Cladosporium uredinicola Phytochemicals

2019 ◽  
Vol 13 ◽  
pp. 13-34
Author(s):  
Melappa Govindappa ◽  
V. Thanuja ◽  
S. Tejashree ◽  
C.A. Soukhya ◽  
Suresh Barge ◽  
...  
Keyword(s):  
Qualitative Method ◽  
Cholinesterase Activity ◽  
Methanol Extract ◽  
High Binding Energy ◽  
Acetyl Cholinesterase ◽  
Gp 120 ◽  
Anti Hiv ◽  
Hiv 1

The present work was aimed to identify phytochemicals in C. uredinicola methanol extract from qualitative, TLC and GC-MS method and evaluated for antioxidant, anti-HIV, anti-diabetes, anti-cholinesterase activity in vitro and in silico. The C. uredinicola extract showed flavonoids, tannins, alkaloids, glycosides, phenols, terpenoids, and coumarins presence in qualitative method. From GC-MS analysis, identified seven different phytochemicals and out of seven, four (coumarin, coumarilic acid, hymecromone, alloisoimperatorin) are coumarins. The C. uredinicola extract have shown significant antioxidant activity in DPPH (73) and FRAP (1359) method. The HIV-1 RT (83.81+2.14), gp 120 (80.24+2.31), integrase (79.43+3.14) and protease (77.63+2.14), DPPIV, β-glucosidase and acetyl cholinesterase activity was significantly reduced by the extract. The 2-diphenylmethyleneamino methyl ester had shown significant interaction with oxidant and HIV-1 proteins whereas alloisoimperatorin have interacted with diabetes and cholinesterase proteins followed by hymecromone with high binding energy. These three phytochemicals are non-carcinogens, non-toxic, readily degradable and have drug likeliness properties. The C. uredinicola phytochemicals are responsible for management of diabetes, HIV-1 and Alzheimer. Further in vivo work is needed to justify our research.

scholarly journals In VitroDrug Combination Studies of Letermovir (AIC246, MK-8228) with Approved Anti-Human Cytomegalovirus (HCMV) and Anti-HIV Compounds in Inhibition of HCMV and HIV Replication

2015 ◽  
Vol 59 (6) ◽  
pp. 3140-3148 ◽  
Author(s):  
Steffen Wildum ◽  
Holger Zimmermann ◽  
Peter Lischka
Keyword(s):  
Human Cytomegalovirus ◽  
Treatment Strategies ◽  
Opportunistic Pathogen ◽  
Multidrug Resistant ◽  
Severe Toxicity ◽  
Transplant Recipients ◽  
Hiv Drugs ◽  
Anti Hiv

ABSTRACTDespite modern prevention and treatment strategies, human cytomegalovirus (HCMV) remains a common opportunistic pathogen associated with serious morbidity and mortality in immunocompromised individuals, such as transplant recipients and AIDS patients. All drugs currently licensed for the treatment of HCMV infection target the viral DNA polymerase and are associated with severe toxicity issues and the emergence of drug resistance. Letermovir (AIC246, MK-8228) is a new anti-HCMV agent in clinical development that acts via a novel mode of action and has demonstrated anti-HCMV activityin vitroandin vivo. For the future, drug combination therapies, including letermovir, might be indicated under special medical conditions, such as the emergence of multidrug-resistant virus strains in transplant recipients or in HCMV-HIV-coinfected patients. Accordingly, knowledge of the compatibility of letermovir with other HCMV or HIV antivirals is of medical importance. Here, we evaluated the inhibition of HCMV replication by letermovir in combination with all currently approved HCMV antivirals using cell culture checkerboard assays. In addition, the effects of letermovir on the antiviral activities of selected HIV drugs, and vice versa, were analyzed. Using two different mathematical techniques to analyze the experimental data, (i) additive effects were observed for the combination of letermovir with anti-HCMV drugs and (ii) no interaction was found between letermovir and anti-HIV drugs. Since none of the tested drug combinations significantly antagonized letermovir efficacy (or vice versa), our findings suggest that letermovir may offer the potential for combination therapy with the tested HCMV and HIV drugs.

Lactoferrin nanoparticles coencapsulated with curcumin and tenofovir improve vaginal defense against HIV-1 infection

Nanomedicine ◽  
2021 ◽  
Author(s):  
Samrajya Lakshmi Yeruva ◽  
Prashant Kumar ◽  
Seetharam Deepa ◽  
Anand K Kondapi
Keyword(s):  
Physicochemical Characterization ◽  
Systemic Circulation ◽  
Application Site ◽  
Drug Nanoparticles ◽  
In Vivo Experiments ◽  
Hiv Microbicide ◽  
Anti Hiv ◽  
Hiv 1

Aim: We report here the development of tenofovir- and curcumin-loaded lactoferrin nanoparticles (TCNPs) as an HIV-microbicide. Materials & methods: TCNPs were subjected to various physicochemical characterization experiments, followed by in vitro and in vivo experiments to assess their efficacy. Results: TCNPs had a diameter of 74.31 ± 2.56 nm with a gross encapsulation of more than 61% for each drug. Nanoparticles were effective against HIV-1 replication, with an IC50 of 1.75 μM for curcumin and 2.8 μM for tenofovir. TCNPs provided drug release at the application site for up to 8–12 h, with minimal leakage into the systemic circulation. TCNPs showed spermicidal activity at ≥200 μM and induced minimal cytotoxicity and inflammation in the vaginal epithelium as revealed by histopathological and ELISA studies. Conclusion: We demonstrated that TCNPs could serve as a novel anti-HIV microbicidal agent in rats. [Formula: see text]

scholarly journals Emergence of Nanotechnology to Fight HIV Sexual Transmission: The Trip of G2-S16 Polyanionic Carbosilane Dendrimer to Possible Pre-Clinical Trials

2020 ◽  
Vol 21 (24) ◽  
pp. 9403
Author(s):  
Ignacio Relaño-Rodríguez ◽  
Maria Ángeles Muñoz-Fernández
Keyword(s):  
Clinical Trials ◽  
Histopathological Examination ◽  
Early Stage ◽  
Sexual Transmission ◽  
Reaction Times ◽  
Vaginal Mucosa ◽  
Carbosilane Dendrimer ◽  
Anti Hiv

Development of new, safe, and effective microbicides to prevent human immunodeficiency virus HIV sexual transmission is needed. Unfortunately, most microbicides proved ineffective to prevent the risk of HIV-infection in clinical trials. We are working with G2-S16 polyanionic carbosilane dendrimer (PCD) as a new possible vaginal topical microbicide, based on its short reaction times, wide availability, high reproducibility, and quantitative yields of reaction. G2-S16 PCD exerts anti-HIV activity at an early stage of viral replication, by blocking gp120/CD4/CCR5 interaction, and providing a barrier against infection for long periods of time. G2-S16 PCD was stable at different pH values, as well as in the presence of seminal fluids. It maintained the anti-HIV activity against R5/X4 HIV over time, did not generate any type of drug resistance, and retained the anti-HIV effect when exposed to semen-enhanced viral infection. Importantly, G2-S16 PCD did not modify vaginal microbiota neither in vitro or in vivo. Histopathological examination did not show vaginal irritation, inflammation, lesions, or damage in the vaginal mucosa, after administration of G2-S16 PCD at different concentrations and times in female mice and rabbit animal models. Based on these promising data, G2-S16 PCD could become a good, safe, and readily available candidate to use as a topical vaginal microbicide against HIV.

scholarly journals Soybean-derived Bowman-Birk Inhibitor (BBI) Inhibits HIV Replication in Macrophages

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Tong-Cui Ma ◽  
Run-Hong Zhou ◽  
Xu Wang ◽  
Jie-Liang Li ◽  
Ming Sang ◽  
...  
Keyword(s):  
Cost Effective ◽  
Peripheral Blood Monocyte ◽  
Type I ◽  
Restriction Factors ◽  
Oligoadenylate Synthetase ◽  
Hiv Replication ◽  
Inhibitory Protein ◽  
Anti Hiv

Abstract The Bowman-Birk inhibitor (BBI), a soybean-derived protease inhibitor, is known to have anti-inflammatory effect in both in vitro and in vivo systems. Macrophages play a key role in inflammation and immune activation, which is implicated in HIV disease progression. Here, we investigated the effect of BBI on HIV infection of peripheral blood monocyte-derived macrophages. We demonstrated that BBI could potently inhibit HIV replication in macrophages without cytotoxicity. Investigation of the mechanism(s) of BBI action on HIV showed that BBI induced the expression of IFN-β and multiple IFN stimulated genes (ISGs), including Myxovirus resistance protein 2 (Mx2), 2′,5′-oligoadenylate synthetase (OAS-1), Virus inhibitory protein (viperin), ISG15 and ISG56. BBI treatment of macrophages also increased the expression of several known HIV restriction factors, including APOBEC3F, APOBEC3G and tetherin. Furthermore, BBI enhanced the phosphorylation of IRF3, a key regulator of IFN-β. The inhibition of IFN-β pathway by the neutralization antibody to type I IFN receptor (Anti-IFNAR) abolished BBI-mediated induction of the anti-HIV factors and inhibition of HIV in macrophages. These findings that BBI could activate IFN-β-mediated signaling pathway, initialize the intracellular innate immunity in macrophages and potently inhibit HIV at multiple steps of viral replication cycle indicate the necessity to further investigate BBI as an alternative and cost-effective anti-HIV natural product.

scholarly journals Efficacies of Entecavir against Lamivudine-Resistant Hepatitis B Virus Replication and Recombinant Polymerases In Vitro

2002 ◽  
Vol 46 (8) ◽  
pp. 2525-2532 ◽  
Author(s):  
S. Levine ◽  
D. Hernandez ◽  
G. Yamanaka ◽  
S. Zhang ◽  
R. Rose ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cross Resistance ◽  
Wild Type ◽  
Resistance Mutations ◽  
Hbv Replication ◽  
B Virus ◽  
Inhibition Studies

ABSTRACT Entecavir (ETV) is a potent and selective inhibitor of hepatitis B virus (HBV) replication in vitro and in vivo that is currently in clinical trials for the treatment of chronic HBV infections. A major limitation of the current HBV antiviral therapy, lamivudine (3TC), is the emergence of drug-resistant HBV in a majority of treated patients due to specific mutations in the nucleotide binding site of HBV DNA polymerase (HBV Pol). To determine the effects of 3TC resistance mutations on inhibition by ETV triphosphate (ETV-TP), a series of in vitro studies were performed. The inhibition of wild-type and 3TC-resistant HBV Pol by ETV-TP was measured using recombinant HBV nucleocapsids, and compared to that of 3TC-TP. These enzyme inhibition studies demonstrated that ETV-TP is a highly potent inhibitor of wild-type HBV Pol and is 100- to 300-fold more potent than 3TC-TP against 3TC-resistant HBV Pol. Cell culture assays were used to gauge the potential for antiviral cross-resistance of 3TC-resistant mutants to ETV. Results demonstrated that ETV inhibited the replication of 3TC-resistant HBV, but 20- to 30-fold higher concentrations were required. To gain further perspective regarding the potential therapeutic use of ETV, its phosphorylation was examined in hepatoma cells treated with extracellular concentrations representative of drug levels in plasma in ETV-treated patients. At these concentrations, intracellular ETV-TP accumulated to levels expected to inhibit the enzyme activity of both wild-type and 3TC-resistant HBV Pol. These findings are predictive of potent antiviral activity of ETV against both wild-type and 3TC-resistant HBV.

scholarly journals A Multiple siRNA-Based Anti-HIV/SHIV Microbicide Shows Protection in Both In Vitro and In Vivo Models

PLoS ONE ◽  
2015 ◽  
Vol 10 (9) ◽  
pp. e0135288 ◽  
Author(s):  
Sandhya Boyapalle ◽  
Weidong Xu ◽  
Payal Raulji ◽  
Subhra Mohapatra ◽  
Shyam S Mohapatra
Keyword(s):  
In Vivo Models ◽  
Anti Hiv
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