IN VITRO EFFECTS OF PR MUTATIONS ON CELL KILLING
It is important to discern whether different protease mutations may result in differences in the cytotoxic effects of drug-resistant PR mutants. We developed a yellow fluorescence protein (YFP) reporter system in which an HIV-1 PR precursor is fused with YFP.
After autocatalytic cleavage of the fusion protein by PR in the transfected cells, a free and toxic PR is formed to induce cytotoxic effects. The toxicity of PR is measured by the YFP density and cell morphology changes of the transfected cells. A panel of PR mutants, which often appear as primary and secondary mutations in PR inhibitor therapy, is generated by site-directed mutagenesis. Our data show that even some single amino acid substitutions are enough to allow PR to lose or reduce its cytotoxic effects in 293 cells (Figure 10.5). These data demonstrate proof of the concept that HIV PR mutations can, independently, alter protease-mediated cytotoxicity.
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