DNA damage enhances integration of HIV-1 into macrophages by overcoming integrase inhibition

Retrovirology

Yukihito Ishizaka²  Masashi Tatsumi⁴  Kenzo Tokunaga³  Binlian Sun¹  Takayoshi Koyama² 

[1] Research Group of HIV Molecular Epidemiology and Virology, The State Key Laboratory of Virology, Wuhan Institution of Virology, Chinese Academy of Sciences, 430071, Wuhan, Hubei, China;Department of Intractable Diseases, National Center for Global Health and Medicine, 1-21-1 Toyama, 162-8655, Shinjuku-ku, Tokyo, Japan;Department of Pathology, National Institute of Infectious Diseases, 1-23-1 Toyama, 162-8640, Shinjuku-ku, Tokyo, Japan;AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, 162-8640, Shinjuku-ku, Tokyo, Japan

关键词: Vpr;    Resting macrophages;    Integration;    Integrase inhibitor;    HIV-1;    DNA damage;   

Others  :  1209160
DOI  :  10.1186/1742-4690-10-21

 received in 2012-06-26, accepted in 2013-02-11,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Koyama et al; licensee BioMed Central Ltd.

【 图 表 】

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