Resistance to Reverse Transcriptase Inhibitors Used in the Treatment and Prevention of HIV-1 Infection

Sluis‐Cremer, Nicolas; Wainberg, Mark A.; Schinazi, Raymond F.

doi:10.2217/fmb.15.106

Cited by 37 publications

(28 citation statements)

References 42 publications

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“…The plasticity of HIV-1 quasispecies allows them to infect different cell targets [8], escape host immunity [9], and resist inhibition by ART [10]. A major challenge for the study of this high level of genetic diversity is the limited capacity of bulk PCR/sequencing techniques to capture the complexity of the viral quasispecies [11].…”

Section: Introductionmentioning

confidence: 99%

Next-generation sequencing of HIV-1 single genome amplicons

Kijak

Sanders‐Buell

Pham

et al. 2019

Biomolecular Detection and Quantification

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The analysis of HIV-1 sequences has helped understand the viral molecular epidemiology, monitor the development of antiretroviral drug resistance, and design candidate vaccines. The introduction of single genome amplification (SGA) has been a major advancement in the field, allowing for the characterization of multiple sequences per patient while preserving linkage among polymorphisms in the same viral genome copy. Sequencing of SGA amplicons is performed by capillary Sanger sequencing, which presents low throughput, requires a high amount of template, and is highly sensitive to template/primer mismatching. In order to meet the increasing demand for HIV-1 SGA amplicon sequencing, we have developed a platform based on benchtop next-generation sequencing (NGS) (IonTorrent) accompanied by a bioinformatics pipeline capable of running on computer resources commonly available at research laboratories. During assay validation, the NGS-based sequencing of 10 HIV-1 env SGA amplicons was fully concordant with Sanger sequencing. The field test was conducted on plasma samples from 10 US Navy and Marine service members with recent HIV-1 infection (sampling interval: 2005–2010; plasma viral load: 5,884–194,984 copies/ml). The NGS analysis of 101 SGA amplicons (median: 10 amplicons/individual) showed within-individual viral sequence profiles expected in individuals at this disease stage, including individuals with highly homogeneous quasispecies, individuals with two highly homogeneous viral lineages, and individuals with heterogeneous viral populations. In a scalability assessment using the Ion Chef automated system, 41/43 tested env SGA amplicons (95%) multiplexed on a single Ion 318 chip showed consistent gene-wide coverage >50×. With lower sample requirements and higher throughput, this approach is suitable to support the increasing demand for high-quality and cost-effective HIV-1 sequences in fields such as molecular epidemiology, and development of preventive and therapeutic strategies.

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Section: Introductionmentioning

confidence: 99%

Next-generation sequencing of HIV-1 single genome amplicons

Kijak

Sanders‐Buell

Pham

et al. 2019

Biomolecular Detection and Quantification

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“…Viral polymerases remain attractive drug targets for the development of selective antiviral therapies [3–5]. Generally, clinically-approved inhibitors that target these proteins fall into two broad classes [6,7]. The first class consists of nucleoside analogues that mimic the natural substrate of the enzyme.…”

Section: Introductionmentioning

confidence: 99%

Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells

Bernatchez

Coste

Beck

et al. 2019

Preprint

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Zika virus (ZIKV), an emerging flavivirus which causes neurodevelopmental impairment 22 to fetuses and has been linked to Guillain-Barré syndrome, continues to threaten global health due 23 to the absence of targeted prophylaxis or treatment. Nucleoside analogues are good examples of 24 efficient anti-viral inhibitors, and prodrug strategies using phosphate masking groups (ProTides) 25 have been employed to improve the bioavailability of ribonucleoside analogues. Here, we 26 synthesized and tested a library of 13 ProTides against ZIKV in human neural stem cells. Strong 27 activity was observed for 2'-C-methyluridine and 2'-C-ethynyluridine ProTides with an aryloxyl 28 phosphoramidate masking group. Conversion of the aryloxyl phosphoramidate ProTide group of 29 2'-C-methyluridine to a 2-(methylthio)ethyl phosphoramidate completely abolished antiviral 30 activity of the compound. The aryloxyl phosphoramidate ProTide of 2'-C-methyluridine 31 outperformed the hepatitis C virus (HCV) drug sofosbuvir in suppression of viral titers and 32 protection from cytopathic effect, while the former compound's triphosphate active metabolite was 33 better incorporated by purified ZIKV NS5 polymerase over time. Molecular superpositioning 34 revealed different orientations of residues opposite the 2'-fluoro group of sofosbuvir. These findings 35 suggest both a nucleobase and ProTide group bias for the anti-ZIKV activity of nucleoside analogue 36 ProTides in a disease-relevant cell model. 37 38 cells, RNA-dependent RNA polymerase 39 40 1. Introduction 41The explosive spread of Zika virus (ZIKV) during the 2015-2016 epidemics in Latin America 42 attracted worldwide attention to this previously neglected disease. The lack of effective vaccines or 43 small molecules to prevent or treat this infection remains a cause for concern and emphasizes the 44 urgent need for new therapeutic options [1]. ZIKV, an emerging flavivirus infection, causes several 48 manifestations of the disease, and in rare cases, ZIKV infection has been linked to the 49 neuroinflammatory Guillain-Barré syndrome [2]. 50 Viral polymerases remain attractive drug targets for the development of selective antiviral 51 therapies [3-5]. Generally, clinically-approved inhibitors that target these proteins fall into two broad 52 classes [6,7]. The first class consists of nucleoside analogues that mimic the natural substrate of the 53 enzyme. Upon analogue incorporation by the virally-encoded polymerase, DNA or RNA synthesis 54 is abrogated by preventing further nucleotide incorporation (chain termination), thereby arresting 55 viral replication. The second class is known as non-nucleoside inhibitors, which bind allosterically 56 and arrest viral nucleic acid synthesis by distorting the polymerase active site geometry to interfere 57 with nucleotide binding or nucleotide incorporation. 58 A common prodrug strategy used for antiviral ribonucleoside analogues involves the chemical 59 synthesis of nucleoside analogue monophosphates with metabolically-removable masking groups 60 [8...

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“…The reverse transcriptase (RT) of the HIV-1 plays a pivotal role in the viral replication process, which makes it a crucial target for anti-HIV-1 inhibitors research (Jonckheere, Anné, De Clercq, 2000;Yisma et al, 2014). In spite of numerous RT inhibitors (including the nucleotide RT inhibitors (NRTIs) and non-nucleotide RT inhibitors (NNRTIs) have been discovered and developed, like other anti-HIV-1 inhibitors, effectiveness of currently approved NRTIs and NNRTIs have been hampered because of their severe side effects and the aggravation of viral variants resistant to HIV-1 drug (Boone, 2006;De Clercq, 2002;Sluis-Cremer, Wainberg, Schinazi, 2015;Yu et al, 2011). To circumvent this challenge, there is an urgent require to develop new, efficacy, selective and safe HIV-1 inhibitors having significant potency against drugresistant RT viral strains and less toxicity still remains a high priority for medical research (Huang et al, 2007;Polanski et al, 2006;Safakish et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and in vitro anti-HIV-1 evaluation of some N-arylsulfonyl-3-formylindoles

Che

Tian

Liu

et al. 2018

Braz. J. Pharm. Sci.

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As our ongoing work on research of anti-HIV-1 inhibitors, fifteen N-arylsulfonyl-3-formylindoles (3ao) were designed and prepared through two step synthetic route. Firstly, 3-formylindoles (2a-c) were synthesized via the Vilsmeier-Haack reaction. Subsequently, treatment of 2a-c with the appropriate arylsulfonyl chlorides led to the corresponding target compounds in excellent yields. All analogues were also preliminary evaluated in vitro for their inhibitory activity against HIV-1 replication. Among of all the reported analogues, three compounds 3c, 3g and 3i displayed significant anti-HIV-1 activity, with EC 50 values of 9.57, 11.04 and 5.02 μM, and TI values of 31. 89, 13.79 and 81.69, respectively. N-mnitrophenylsulfonyl-3-formylindole (3c) and N-m-nitrophenylsulfonyl-6-methyl-3-formylindole (3i) especially exhibited the best promising anti-HIV-1 activity. In addition, it demonstrated that insertion of a methyl group at the C-6 position of the indolyl ring and a nitro group at the meta position of the arylsulfonyl ring, as in compound 3i, resulted in both low cytotoxicity (CC 50 = 410.41 μM) and good antiviral activity.

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Resistance to Reverse Transcriptase Inhibitors Used in the Treatment and Prevention of HIV-1 Infection

Cited by 37 publications

References 42 publications

Next-generation sequencing of HIV-1 single genome amplicons

Next-generation sequencing of HIV-1 single genome amplicons

Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells

Synthesis and in vitro anti-HIV-1 evaluation of some N-arylsulfonyl-3-formylindoles

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