HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration

It is known that CD4+ helper T cells, key immune regulators, are eliminated by HIV-1 infection, but how the virus causes cell death has been unclear. Here Gary Nabel and colleagues show that HIV-1 integration is both necessary and sufficient to trigger CD4+ T-cell death, and that integration triggers cell death through activation of DNA-dependent protein kinase (DNA-PK), part of the DNA repair mechanism, and phosphorylation of p53. This work may help to explain how reservoirs of virus are established in HIV-infected subjects, and suggests that treatment with integrase or DNA-PK inhibitors might prolong CD4 cell survival and delay the development of AIDS.