A novel mutation, D404N, in the connection subdomain of reverse transcriptase of HIV-1 CRF08_BC subtype confers cross-resistance to NNRTIs

Zhang, Xiaomin; Wu, Hao; Zhang, Qiwei; Lau, Terrence Chi-Kong; Chu, Hin; Chen, Zhiwei; Jin, Dong-Yan; Zheng, Bo‐Jian

doi:10.1093/jac/dku565

Cited by 5 publications

(8 citation statements)

References 40 publications

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“…14 In a later study, we demonstrated that D404N in the RT connection subdomain was an NNRTI resistance-related mutation that displayed cross-resistance to NVP, EFV, rilpivirine (RPV), and AZT. 16 In this study, we extended our research to the other two novel mutations, L228I and Y232H. Both these mutations locate in the b12-b13 hairpin of the palm subdomain, which contains the residues 227-235 (FLWMGYELH) and forms the so-called primer grip in RT.…”

Section: Introductionmentioning

confidence: 92%

“…Six mutation patterns, including L228I, Y188C, Y188C/ L228I, A139V, Y232H, and A139V/Y232H, in RT were introduced into the pBRGX plasmid by site-directed mutagenesis as described previously. 16 Multiple mutations were introduced into pBRGX one by one. The presence of desired mutations in the plasmids was confirmed by DNA sequencing.…”

Section: Site-directed Mutagenesis and Virus Productionmentioning

confidence: 99%

“…The susceptibility of virus variants to NNRTIs (NVP, EFV, and ETR) and NRTIs (AZT, ABC, 3TC, FTC, and TDF) was measured in a single-cycle cell culture-based phenotypic assay in TZM-bl cells as described previously. 16 In brief, 1 · 10 4 cells were seeded on a 96-well flat-bottom plate in 100 ll of growth medium (Dulbecco's modified Eagle's medium +10% fetal bovine serum +1% penicillin/ streptomycin). Next day, mutant and WT viruses equal to 200-400 blue focus forming unit in serially diluted drugs were added into each well of the plate in triplicate.…”

Section: Phenotypic Susceptibility Of Virus Variantsmentioning

confidence: 99%

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Novel Mutations L228I and Y232H Cause Nonnucleoside Reverse Transcriptase Inhibitor Resistance in Combinational Pattern

Zhang

et al. 2016

AIDS Research and Human Retroviruses

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The emergence of drug resistance mutations is increasing after the implementation of highly active antiretroviral therapy. To characterize two novel mutations L228I and Y232H in the primer grip of reverse transcriptase (RT) of HIV-1 circulating recombination form 08_BC (CRF08_BC) subtype, both mutant clones were constructed to determine their impacts on viral phenotypic susceptibility and replication capacity (RC). Results showed that the novel mutation, L228I, conferred a low-level resistance to etravirine by itself. L228I in combination with Y188C displayed a high level of cross-resistance to both nevirapine (NVP) and efavirenz (EFV). The copresence of A139V and Y232H induced a moderate level of resistance to NVP and EFV. Mutations Y188C/L228I, A139V, Y232H, and A139V/Y232H reduced more than 55% of viral RC compared with that of the wild-type (WT) reference virus. Modeling study suggested that the copresence of Y188C/L228I or A139V/Y232H might induce conformational changes to RT, which might result in reduced drug susceptibility and viral RC due to abolished hydrogen bonding or complex interaction with vicinal residues. Our results demonstrated that L228I and Y232H were novel accessory nonnucleoside reverse transcriptase inhibitor resistance-related mutations and provided valuable information for clinicians to design more effective treatment to patients infected with HIV-1 subtype CRF08_BC.

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Section: Introductionmentioning

confidence: 92%

Section: Site-directed Mutagenesis and Virus Productionmentioning

confidence: 99%

Section: Phenotypic Susceptibility Of Virus Variantsmentioning

confidence: 99%

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Novel Mutations L228I and Y232H Cause Nonnucleoside Reverse Transcriptase Inhibitor Resistance in Combinational Pattern

Zhang

et al. 2016

AIDS Research and Human Retroviruses

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“…Ultra-wide sequencing of the full-length viral genome, generating additional information on amino acid substitutions in Gag, Pol and Env, could enhance therapeutic outcome predictions [22][23][24][25][26][27].…”

Section: Ultra-wide Ngs For Genotypic Drug Resistance Testingmentioning

confidence: 99%

HIV-1 genotypic drug resistance testing: digging deep, reaching wide?

Laethem

Theys

Vandamme

2015

Current Opinion in Virology

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For many years, population-based Sanger sequencing has been the golden standard for drug resistance testing within the routine follow-up of HIV-1 infected patients in resource-rich settings. Often, the data generated within this framework were subsequently used for research and surveillance purposes: to understand therapy response and to gain insights into epidemiological processes. Sanger sequencing was however ill suited for diagnostic and prognostic use in resource-limited settings (RLS) and therefore not broadly implemented. Next-generation sequencing (NGS) technologies provide high-throughput approaches by the rapid acquisition of thousands to millions of short nucleotide sequences. Depending on the experimental design, the roll-out of NGS drug resistance testing at a larger scale is feasible, providing better characterization and understanding of the evolving population of viral variants within a patient and potentially improving the prognostic value of drug resistance testing. Whether the same will become true for RLS will largely depend on affordability and sample logistics, and this may affect other mutation-specific approaches.

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“…Unlike the marketed NNRTIs (Ren and Stammers 2008;Agneskog et al 2013;Sluis-Cremer 2014;Gallien et al 2015;Zhang et al 2015), W-1 exhibited more potent antiviral activity against NNRTIs-resistant HIV-1 strains (Lu et al 2007;Qin et al 2010). Therefore W-1 could have the potential to be next generation of drug candidate for treatment of acquired immunodeficiency syndrome (AIDS).…”

Section: Introductionmentioning

confidence: 99%

Profile of disposition, tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats

Wang

et al. 2016

Arch. Pharm. Res.

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The purpose of this study was to characterize the disposition, distribution, excretion and plasma protein binding of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1) in rats. Concentrations of W-1 within biological samples were determined using a validated high performance liquid chromatography method. The plasma protein binding of W-1 was examined by equilibrium dialysis method. After oral administration of W-1 (50, 100 and 200 mg/kg, respectively) in self-microemulsifying drug delivery system formulation, the pharmacokinetic parameters of W-1 were as follows: the peak plasma concentrations (C max) were 0.42, 1.50 and 2.55 μg/mL, the area under the curve (AUC0-t) were 0.89, 2.27 and 3.96 µg/h mL and the plasma half-life (t 1/2) were 5.15, 3.77 and 3.77 h, respectively. Moreover, the prototype of W-1 was rapidly and extensively distributed into fifteen tissues, especially higher concentrations were detected in intestine, stomach and liver, respectively. The plasma protein binding of W-1 in rat, beagle dog and human were in the range of 97.96-99.13 %. This study suggested that W-1 has an appropriate pharmacokinetics in rats, such as rapid absorption, moderate clearance, and rapid distribution to multiple tissues. Those properties provide important information for further development W-1 as an anti-HIV-1 drug candidate.

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A novel mutation, D404N, in the connection subdomain of reverse transcriptase of HIV-1 CRF08_BC subtype confers cross-resistance to NNRTIs

Abstract: These results indicate that D404N is a novel NNRTI-associated mutation in the HIV-1 subtype CRF08_BC and provides information valuable for the monitoring of clinical RTI resistance.

Cited by 5 publications

References 40 publications

Novel Mutations L228I and Y232H Cause Nonnucleoside Reverse Transcriptase Inhibitor Resistance in Combinational Pattern

Novel Mutations L228I and Y232H Cause Nonnucleoside Reverse Transcriptase Inhibitor Resistance in Combinational Pattern

HIV-1 genotypic drug resistance testing: digging deep, reaching wide?

Profile of disposition, tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats

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