Abstract
At present, treatment of HIV infection uses small inhibitory molecules that target HIV protease; however, the emergence of resistant HIV strains is increasingly problematic. To circumvent this, we report here a new 'Trojan horse' strategy to kill HIV-infected cells by exploiting HIV protease. We engineered 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 uninfected cells. In HIV-infected cells, TAT–Casp3 becomes processed into an active form by HIV protease, resulting in apoptosis of the infected cell. This strategy could also be applied to other pathogens encoding specific proteases, such as hepatitis C virus, cytomegalovirus and malaria.
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Acknowledgements
We thank E.S. Alnemri for the human Casp3 cDNA; K. Wang for help with DEVD-AFC reactions; Abbott Labs for Ritonavir; S. Horning for doing the TUNEL assays; and D. Goldberg, C. Rice, S. Virgin and all the members of the Dowdy and Ratner labs for critical input. This work was supported by the N.I.H. (L.R.) and the Howard Hughes Medical Institute (S.F.D.). S.F.D. is an Assistant Investigator of the Howard Hughes Medical Institute.
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Vocero-Akbani, A., Heyden, N., Lissy, N. et al. Killing HIV-infected cells by transduction with an HIV protease-activated caspase-3 protein. Nat Med 5, 29–33 (1999). https://doi.org/10.1038/4710
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DOI: https://doi.org/10.1038/4710
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