title: DNA damage enhances integration of HIV-1 into macrophages by overcoming integrase inhibition.
abstract: BACKGROUND
  The prevention of persistent human immunodeficiency virus type 1 (HIV-1) infection requires the clarification of the mode of viral transduction into resting macrophages. Recently, DNA double-strand breaks (DSBs) were shown to enhance infection by D64A virus, which has a defective integrase catalytic activity (IN-CA). However, the mechanism by which DSBs upregulate viral transduction was unclear. Here we analyzed the roles of DSBs during IN-CA-independent viral transduction into macrophages.
  
  
  RESULTS
  We used cellular systems with rare-cutting endonucleases and found that D64A virus integrated efficiently into the sites of artificially induced DSBs. This IN-CA-independent viral transduction was blocked by an inhibitor of ataxia telangiectasia mutated protein (ATM) but was resistant to raltegravir (RAL), an inhibitor of integrase activity during strand transfer. Moreover, Vpr, an accessory gene product of HIV-1, induced DSBs in resting macrophages and significantly enhanced the rate of IN-CA-independent viral transduction into macrophages with concomitant production of secondary viruses.
  
  
  CONCLUSIONS
  DSBs contribute to the IN-CA-independent viral infection of macrophages, which is resistant to RAL. Thus, the ATM-dependent cellular pathway and Vpr-induced DNA damage are novel targets for preventing persistent HIV-1 infection.
authors: Department of Intractable Diseases, National Center for Global Health and Medicine, 1-21-1 Toyama, 162-8655, Shinjuku-ku, Tokyo, Japan.
authors: Takayoshi
authors: T
authors: Koyama
authors: Binlian
authors: B
authors: Sun
authors: Kenzo
authors: K
authors: Tokunaga
authors: Masashi
authors: M
authors: Tatsumi
authors: Yukihito
authors: Y
authors: Ishizaka
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D024882:Drug Resistance, Viral; D057809:HEK293 Cells; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000201:enzymology / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D019429:Integrase Inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism / Q000821:virology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D000068898:Raltegravir Potassium; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D016662:Virus Integration / Q000235:genetics / Q000502:physiology*; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D019429:Integrase Inhibitors; D011760:Pyrrolidinones; D025521:Tumor Suppressor Proteins; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1; D000068898:Raltegravir Potassium; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1