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Complementation in Cells Cotransfected with a Mixture of Wild-Type and Mutant Human Immunodeficiency Virus (HIV) Influences the Replication Capacities and Phenotypes of Mutant Variants in a Single-Cycle HIV Resistance Assay

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois

Received 30 October 2003/ Returned for modification 5 May 2004/ Accepted 5 June 2004

The impact of cotransfection of mixtures of mutant and wild type (WT) virus on the observed phenotype and replication capacity (RC) in a single-cycle human immunodeficiency virus (HIV) phenotypic assay has been investigated by cotransfecting mutant HIV clones expressing the firefly luciferase expression gene with a WT clone expressing Renilla luciferase. Four mutant constructs with different genotypes displayed <1% RC when transfected alone. Cotransfection of as little as 9% of the WT clone resulted in an 18- to 33-fold increase in the RC of the mutant clones. In addition, the 50% inhibitory concentration (IC₅₀) of lopinavir against seven mutant clones decreased by up to 97% after incremental cotransfection of 9 to 50% of the WT clone. The enhancement of RC and decrease in IC₅₀ for mutant variants following cotransfection with the WT variant appear to be due to complementation rather than genetic recombination. These findings suggest that the RC and susceptibility of plasma isolates from patients who are off therapy or not adherent to treatment, in which WT virus may expand to significant levels, should be interpreted with caution.

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