HIV virus kills CD4+ T cells, ultimately impairing the function of the immune system. It now appears that the death of these cells results from the integration of the provirus into the genome and is mediated by a signaling pathway involving the ATM/ATR family kinase DNA-PK. Inhibition of DNA-PK prevent HIV-induced apoptotic death, but actually enhances DNA damage-induced death, showing that it plays opposing roles in the response to different forms of DNA damage stress.