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

Takayoshi Koyama1, Binlian Sun2, Kenzo Tokunaga3, Masashi Tatsumi4 and Yukihito Ishizaka1*

Author Affiliations

1 Department of Intractable Diseases, National Center for Global Health and Medicine, 1-21-1 Toyama, 162-8655, Shinjuku-ku, Tokyo, Japan

2 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

3 Department of Pathology, National Institute of Infectious Diseases, 1-23-1 Toyama, 162-8640, Shinjuku-ku, Tokyo, Japan

4 AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, 162-8640, Shinjuku-ku, Tokyo, Japan

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Retrovirology 2013, 10:21  doi:10.1186/1742-4690-10-21

Published: 21 February 2013



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.


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.


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.

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