Computational analysis of retrovirus-induced scid cell death.
It was shown recently that retroviral infection induces integrase-dependent apoptosis (programmed cell death) in DNA-dependent protein kinase (DNA-PK)-deficient scid pre-B cell lines, and it has been proposed that retroviral DNA integration is perceived as DNA damage that is repairable by the DNA-PK-dependent nonhomologous end-joining pathway (R. Daniel, R. A. Katz, and A. M. Skalka, Science 284:644-647, 1999). Very few infectious virions seem to be necessary to induce scid cell death. In this study, we used a modeling approach to estimate the number of integration events necessary to induce cell death of DNA-PK-deficient scid cells. Several models for integration-mediated cell killing were considered. Our analyses indicate that a single hit (integration event) is sufficient to kill a scid cell. Moreover, the closest fit between the experimental data and our computational simulations was achieved with a model in which the infected scid cell must pass through S phase to trigger apoptosis. This model is consistent with the findings that a single double-strand DNA break is sufficient to kill a cell deficient in DNA repair and illustrates the potential of a modeling approach to address quantitative aspects of virus-cell interactions.
Daniel
R
R
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Litwin
S
S
Katz
R A
RA
Skalka
A M
AM
D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D004261:DNA Replication; D008433:Mathematics; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D012190:Retroviridae / Q000502:physiology*; D016662:Virus Integration