Fig. 6

Sensitivity of CD4 T cells derived from virally infected individuals and HS to CPT-induced apoptosis, and a novel model of virus-induced disruption of DNA topology in T cell dysregulation. a Vulnerability of CD4 T cells, derived from virally infected individuals and HS, to the CPT-induced apoptosis as measured by flow cytometry. b A working model for Top 1-mediated DDR and T cell dysregulation during HIV infection. The intertwined nature of two complementary DNA often lead to topological entanglements during gene transcription and replication that must be resolved to ensure normal gene transactions and cell functions. In order to prevent and correct these types of topological problems, Top 1 binds to DNA and cuts one DNA strand, allowing the DNA to be untangled or unwound so as to exert genetic activities. According on our results, the immunomodulatory virus (HCV, HBV, HIV) infection and/or CPT treatment can inhibit Top 1 protein expression and enzymatic activity, leading to Top1cc trapped at the DNA breaks including telomere termini and causing topological DNA damage, telomere loss, cell senescence and apoptosis. This regulatory cascade represents a novel molecular mechanism that underlies T cell senescence and T cell dysfunction, which contribute to viral persistence and vaccine non-responsiveness in human viral infections