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Chapter 16 : Phenotypic Susceptibility Assays for Human Immunodeficiency Virus Type 1

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Phenotypic Susceptibility Assays for Human Immunodeficiency Virus Type 1, Page 1 of 2

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Abstract:

Phenotypic susceptibility assays are used in the laboratory to measure the susceptibility of a virus to an antiviral agent. They are used for some viruses, such as human immunodeficiency virus type 1 (HIV-1), in clinical settings to help construct the drug regimen most active against an individual patient’s virus. This chapter summarizes the technology behind commonly used antiviral drug susceptibility assays for HIV-1 and the interpretation of results generated by them. Currently there are two approved anti-HIV drugs that target virus entry: the fusion inhibitor enfuvirtide (ENF) and the CCR5 coreceptor antagonist maraviroc. The chapter describes phenotypic assays for determining HIV-1 coreceptor tropism. Assays that determine HIV-1 viral tropism in a patient are needed to allow the clinician to make an informed decision as to whether a CCR5 co-receptor antagonist is an appropriate drug choice for a given patient. Two standardized MT-2 assay approaches have been described. In the first, viral stocks from stimulated patient lymphocytes co-cultured with lymphocytes from an HIV-negative donor are generated. The second method utilizes direct cocultivation of patient lymphocytes with MT-2 cells, followed by microscopic examination. Currently approved, interferon/ribavirin-based treatment of hepatitis C virus (HCV) infection is incompletely effective and is associated with significant toxicity and tolerability issues. Approaches to measure HCV drug susceptibility can be broadly classified into four categories: (i) intact virus assays, (ii) replicon-based recombinant virus assays (RVAs), (iii) cell-based (nonreplicon) assays, and (iv) enzymatic assays. Phenotypic assays are useful during preclinical development, clinical development, and potentially in clinical practice.

Citation: Parkin N, Coakley E, Petropoulos C. 2009. Phenotypic Susceptibility Assays for Human Immunodeficiency Virus Type 1, p 283-299. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch16

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Figure 1. (A)

Typical susceptibility curve for a competitive inhibitor (solid line); reduction in susceptibility is manifested as an increase in IC (dashed line). (B) Susceptibility curve for a noncompetitive inhibitor (solid line); reduction in susceptibility is exhibited by a plateau at less than 100% maximal inhibition (dashed line).

Citation: Parkin N, Coakley E, Petropoulos C. 2009. Phenotypic Susceptibility Assays for Human Immunodeficiency Virus Type 1, p 283-299. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch16
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Tables

Generic image for table
Table 1.

Phenotypic assays for HIV PR and RT inhibitor susceptibility

Citation: Parkin N, Coakley E, Petropoulos C. 2009. Phenotypic Susceptibility Assays for Human Immunodeficiency Virus Type 1, p 283-299. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch16
Generic image for table
Table 2.

Phenotypic susceptibility cutoffs

Citation: Parkin N, Coakley E, Petropoulos C. 2009. Phenotypic Susceptibility Assays for Human Immunodeficiency Virus Type 1, p 283-299. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch16
Generic image for table
Table 3.

Key technical characteristics of recombinant tropism assays that are available in the clinic or in development

Citation: Parkin N, Coakley E, Petropoulos C. 2009. Phenotypic Susceptibility Assays for Human Immunodeficiency Virus Type 1, p 283-299. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch16
Generic image for table
Table 4.

Prevalence of R5 and X4 viruses in treatment-naive and -experienced HIV-1-infected patients

Citation: Parkin N, Coakley E, Petropoulos C. 2009. Phenotypic Susceptibility Assays for Human Immunodeficiency Virus Type 1, p 283-299. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch16
Generic image for table
Table 5.

Comparison of 24-week CCR5 antagonist efficacy in treatment-experienced patients

Citation: Parkin N, Coakley E, Petropoulos C. 2009. Phenotypic Susceptibility Assays for Human Immunodeficiency Virus Type 1, p 283-299. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch16

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