論文 - 詳細
| RRC ID | 69180 |
|---|---|
| 著者 | Koyama T, Sun B, Tokunaga K, Tatsumi M, Ishizaka Y. |
| タイトル | DNA damage enhances integration of HIV-1 into macrophages by overcoming integrase inhibition. |
| ジャーナル | Retrovirology |
| 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. CONCLUSION: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. |
| 巻・号 | 10 |
| ページ | 21 |
| 公開日 | 2013-2-21 |
| DOI | 10.1186/1742-4690-10-21 |
| PII | 1742-4690-10-21 |
| PMID | 23432899 |
| PMC | PMC3605128 |
| MeSH | Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism Cell Line DNA Breaks, Double-Stranded DNA Damage / physiology* DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Drug Resistance, Viral HEK293 Cells HIV Integrase / genetics HIV Integrase / metabolism* HIV-1 / enzymology HIV-1 / pathogenicity* HIV-1 / physiology Humans Integrase Inhibitors / pharmacology Macrophages / metabolism Macrophages / virology* Protein Serine-Threonine Kinases / genetics Protein Serine-Threonine Kinases / metabolism Pyrrolidinones / pharmacology Raltegravir Potassium Tumor Suppressor Proteins / genetics Tumor Suppressor Proteins / metabolism Virus Integration / genetics Virus Integration / physiology* vpr Gene Products, Human Immunodeficiency Virus / genetics vpr Gene Products, Human Immunodeficiency Virus / metabolism |
| IF | 4.183 |
| リソース情報 | |
| ヒト・動物細胞 | THP-1(RCB1189) 293(RCB1637) 293T(RCB2202) |