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 a pproach to estimate the number of integration events necessary to induce ce ll death of DNA-PK-deficient scid cells. Several models for integration-med iated cell killing were considered, Our analyses indicate that a single hit (integration event) is sufficient to kill a scid cell. Moreover, the close st fit between the experimental data and our computational simulations was achieved with a model in which the infected scid cell must pass through S p hase 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.