Chapter 112 : Susceptibility Test Methods: Viruses*

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Susceptibility Test Methods: Viruses*, Page 1 of 2

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This chapter describes the phenotypic and genotypic methods that are being used to perform viral susceptibility tests and situations when testing should be considered. The phenotypic method section consists of classic methods that are still in use, such as plaque assays. Newer methods such as recombinant virus assays (RVAs) that use both a molecular and phenotypic approach are also described. The genotypic methods section describes the various sequencing platforms and reverse-hybridization assays that are commonly used. There is a paucity of FDA-approved/cleared kits available. Therefore, other kits/reagents including research-use only (RUO) and laboratory-developed tests (LDTs) using analyte-specific reagents (ASRs) are also included in the discussion. Descriptions of the genotypic assays include the reported mutations associated with antiviral resistance for selected viruses. Finally, there is a discussion of the knowledge-based expert systems available for the clinical interpretation of sequence data. This document should be useful if a clinical diagnostic laboratory chooses to develop an LDT antiviral genotypic assay.

Citation: Huang D, Bankowski M. 2015. Susceptibility Test Methods: Viruses*, p 1913-1931. In Jorgensen J, Pfaller M, Carroll K, Funke G, Landry M, Richter S, Warnock D (ed), Manual of Clinical Microbiology, Eleventh Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817381.ch112
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Example of a PRA (i.e., phenotypic test) used for determining acyclovir resistance in HSV-1. The reduction in the number of plaques is shown for an acyclovir-sensitive HSV-1 tested in duplicate starting with uninfected cells in the first two wells (1A/1B). Increasing acyclovir concentration is added downward to duplicate wells beginning with 2A/2B to 3A/3B and continuing from the top, right downward (1C/1D to 3C/3D) of the 12-well microtiter plate. The lowest number of plaques appears in wells 3C/3D where the highest concentration of acyclovir is added. doi:10.1128/9781555817381.ch112.f1

Citation: Huang D, Bankowski M. 2015. Susceptibility Test Methods: Viruses*, p 1913-1931. In Jorgensen J, Pfaller M, Carroll K, Funke G, Landry M, Richter S, Warnock D (ed), Manual of Clinical Microbiology, Eleventh Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817381.ch112
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Image of FIGURE 2

General protocol for sequence-based genotypic assays of plasma samples. The individual steps that are performed in sequence-based genotypic assays are shown. Above the first line are components that are accomplished as a result of specified protocol instructions and machinery. After completion of the block, the subsequent steps are performed with subjective input from the operator within a software program that will accept the chromatograms generated by the sequencer. The operator then chooses the portion of the reference sequence containing the unknown mutations for use in the software of their choice. This is followed by alignment and editing of the sequences to identify these mutations in the patient samples. The most commonly used consensus sequences of HIV-1 strains are either HIV-1 strain HXB2 or HIV-1 consensus B. If the operator is using an in-house genotyping assay for other viruses, the reference sequence used should be based upon the literature or “common practice.” doi:10.1128/9781555817381.ch112.f2

Citation: Huang D, Bankowski M. 2015. Susceptibility Test Methods: Viruses*, p 1913-1931. In Jorgensen J, Pfaller M, Carroll K, Funke G, Landry M, Richter S, Warnock D (ed), Manual of Clinical Microbiology, Eleventh Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817381.ch112
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Clinical situations where antiviral resistance testing may be indicated

Citation: Huang D, Bankowski M. 2015. Susceptibility Test Methods: Viruses*, p 1913-1931. In Jorgensen J, Pfaller M, Carroll K, Funke G, Landry M, Richter S, Warnock D (ed), Manual of Clinical Microbiology, Eleventh Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817381.ch112
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Proposed guidelines for antiviral susceptibility results of herpes group and influenza A viruses

Citation: Huang D, Bankowski M. 2015. Susceptibility Test Methods: Viruses*, p 1913-1931. In Jorgensen J, Pfaller M, Carroll K, Funke G, Landry M, Richter S, Warnock D (ed), Manual of Clinical Microbiology, Eleventh Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817381.ch112
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Gene targets used for antiviral resistance testing with genotypic methods

Citation: Huang D, Bankowski M. 2015. Susceptibility Test Methods: Viruses*, p 1913-1931. In Jorgensen J, Pfaller M, Carroll K, Funke G, Landry M, Richter S, Warnock D (ed), Manual of Clinical Microbiology, Eleventh Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817381.ch112
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CMV UL54 and UL97 gene targets and the associated mutations conferring antiviral resistance

Citation: Huang D, Bankowski M. 2015. Susceptibility Test Methods: Viruses*, p 1913-1931. In Jorgensen J, Pfaller M, Carroll K, Funke G, Landry M, Richter S, Warnock D (ed), Manual of Clinical Microbiology, Eleventh Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817381.ch112
Generic image for table

Bioinformatics-based sites for analysis of resistance from genotyped samples

Citation: Huang D, Bankowski M. 2015. Susceptibility Test Methods: Viruses*, p 1913-1931. In Jorgensen J, Pfaller M, Carroll K, Funke G, Landry M, Richter S, Warnock D (ed), Manual of Clinical Microbiology, Eleventh Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817381.ch112

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