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

• Published in: Nature (London) Vol. 498; no. 7454; pp. 376 - 379
• Main Authors: Cooper, Arik, García, Mayra, Petrovas, Constantinos, Yamamoto, Takuya, Koup, Richard A., Nabel, Gary J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.06.2013; Nature Publishing Group
• Subjects: 631/326/421; Carrier State - virology; CD4 lymphocytes; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; CD4-Positive T-Lymphocytes - virology; Cell death; Cell Death - drug effects; Cell Line; Cell Survival - drug effects; Cells, Cultured; DNA Damage; DNA Repair; DNA-Activated Protein Kinase - antagonists & inhibitors; DNA-Activated Protein Kinase - metabolism; Enzyme Activation; Histones - metabolism; HIV infection; HIV Infections - pathology; HIV Infections - virology; HIV Integrase Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - growth & development; HIV-1 - pathogenicity; Human immunodeficiency virus 1; Human Immunodeficiency Virus Proteins - analysis; Human Immunodeficiency Virus Proteins - genetics; Humanities and Social Sciences; Humans; letter; Macaca; multidisciplinary; Observations; Phosphorylation; Properties; Protein kinases; Proviruses - pathogenicity; Pyrrolidinones - pharmacology; Raltegravir Potassium; Science; Testing; Tumor Suppressor Protein p53 - metabolism; Virus Integration; Virus Replication - drug effects; United States
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature12274

HIV-1 causes CD4 + T-cell death through viral integration by stimulation of DNA-dependent protein kinase (DNA-PK), a protein known to act in the p53 damage response pathway for double-stranded DNA breaks, in activated cells. How HIV-1 causes cell death 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. Human immunodeficiency virus-1 (HIV-1) has infected more than 60 million people and caused nearly 30 million deaths worldwide 1 , ultimately the consequence of cytolytic infection of CD4 + T cells. In humans and in macaque models, most of these cells contain viral DNA and are rapidly eliminated at the peak of viraemia 2 , 3 , 4 , yet the mechanism by which HIV-1 induces helper T-cell death has not been defined. Here we show that virus-induced cell killing is triggered by viral integration. Infection by wild-type HIV-1, but not an integrase-deficient mutant, induced the death of activated primary CD4 lymphocytes. Similarly, raltegravir, a pharmacologic integrase inhibitor, abolished HIV-1-induced cell killing both in cell culture and in CD4 + T cells from acutely infected subjects. The mechanism of killing during viral integration involved the activation of DNA-dependent protein kinase (DNA-PK), a central integrator of the DNA damage response, which caused phosphorylation of p53 and histone H2AX. Pharmacological inhibition of DNA-PK abolished cell death during HIV-1 infection in vitro , suggesting that processes which reduce DNA-PK activation in CD4 cells could facilitate the formation of latently infected cells that give rise to reservoirs in vivo . We propose that activation of DNA-PK during viral integration has a central role in CD4 + T-cell depletion, raising the possibility that integrase inhibitors and interventions directed towards DNA-PK may improve T-cell survival and immune function in infected individuals.