Genotype and Phenotype


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Genotype and Phenotype

Resistance testing generally involves determining the genotype or phenotype of a virus. The genotype refers to the sequence of nucleotides in the viral genome that determine the genes of the virus. Genotypic assays are assays that determine the nucleotide sequence of specific genes, or parts of genes. Viruses that have the same gene sequence as other viruses found in nature (for example, from patients who never received antiretroviral therapy) are considered to be Awild type@. Genetic differences (mutations) that arise during the course of antiretroviral therapy are considered to be drug resistance mutations if the presence of these mutations reduces the susceptibility of the virus to a particular drug. In some cases the nucleotide sequence at a particular position in a gene may vary from one isolate to the next, even in the absence of any drug treatment. Such differences are often referred to as polymorphisms.

The phenotype refers to the characteristics or properties of the virus. Phenotypic assays for drug susceptibility determine the amount of drug needed to inhibit viral growth in tissue culture. The amount of drug needed to inhibit virus growth by 50% is called the 50% inhibitory concentration, or IC50; similarly, the concentration of drug that inhibits virus growth by 95% is known as the IC95. Testing a particular drug against a large number of isolates from patients who never received antiretroviral therapy can determine average IC50 for wild-type isolates of HIV-1. Viruses that are inhibited by similar concentrations of that drug are considered susceptible or sensitive; those that are inhibited only at higher drug concentrations are considered resistant.

Results of phenotypic assays are sometimes expressed as Afold-resistance@ by comparing the IC50 of the patient=s virus to that of a control isolate. For example, if the IC50 for zidovudine of the control isolate is 2 nM and the patient isolate has an IC50 of 20 nM, then the patient=s virus would be 10-fold resistant as compared to the control. However, the definition of Aresistant@ also needs to consider the concentration of drug that can be achieved in the plasma and the relationship between IC50 or fold-resistance and clinical response to the drug in question.

4/15/01