Killing HIV-infected cells by transduction with an HIV protease-activated caspase-3 protein

At present, treatment of HIV infection uses small inhibitory molecules that target HIV protease; however, the emergence of resistant HIV strains is in creasingly problematic. To circumvent this, we report here a new 'Trojan ho rse' strategy to kill HIV-infected cells by exploiting HIV protease. We eng ineered a transducing, modified, apoptosis-promoting caspase-3 protein, TAT -Casp3, that substitutes HIV proteolytic cleavage sites for endogenous ones and efficiently transduces about 100% of cells, but remains inactive in un infected cells. In HIV-infected cells, TAT-Casp3 becomes processed into an active form by HIV protease, resulting in apoptosis of the infected cell. T his strategy could also be applied to other pathogens encoding specific pro teases, such as hepatitis C virus, cytomegalovirus and malaria.