title: HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration.
abstract: Human immunodeficiency virus-1 (HIV-1) has infected more than 60 million people and caused nearly 30 million deaths worldwide, 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, 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.
authors.affiliation: Virology Laboratory, Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-3005, USA.
authors.forename: Arik
authors.initials: A
authors.lastname: Cooper
authors.forename: Mayra
authors.initials: M
authors.lastname: García
authors.forename: Constantinos
authors.initials: C
authors.lastname: Petrovas
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Nabel
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D002353:Carrier State / Q000821:virology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004789:Enzyme Activation; D015658:HIV Infections / Q000473:pathology / Q000821:virology; D019428:HIV Integrase Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity*; D006657:Histones / Q000378:metabolism; D054298:Human Immunodeficiency Virus Proteins / Q000032:analysis / Q000235:genetics; D006801:Humans; D010766:Phosphorylation; D011533:Proviruses / Q000472:pathogenicity*; D011760:Pyrrolidinones / Q000494:pharmacology; D000068898:Raltegravir Potassium; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D016662:Virus Integration; D014779:Virus Replication / Q000187:drug effects
chemical_list: C468783:H2AX protein, human; D019428:HIV Integrase Inhibitors; D006657:Histones; D054298:Human Immunodeficiency Virus Proteins; D011760:Pyrrolidinones; D016159:Tumor Suppressor Protein p53; D000068898:Raltegravir Potassium; D051747:DNA-Activated Protein Kinase