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HIV-1 Vpr Induces DNA Double-Strand Breaks

¹ Graduate School of Science and Engineering, Waseda University; ² Department of Intractable Diseases, International Medical Center of Japan; and ³ Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan

Requests for reprints: Hitoshi Kurumizaka, Graduate School of Science and Engineering, Waseda University, 3-4-1 Okubo, Shinjuku-ku, 169-8555 Tokyo, Japan. Phone: 81-3-5286-8189; Fax: 81-3-5292-9211; E-mail: kurumizaka{at}waseda.jp and Yukihito Ishizaka, Department of Intractable Diseases, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, 162-8655 Tokyo, Japan. Phone: 81-3-5272-7527; E-mail: zakay{at}ri.imcj.go.jp.

Recent observations imply that HIV-1 infection induces chromosomal DNA damage responses. However, the precise molecular mechanism and biological relevance are not fully understood. Here, we report that HIV-1 infection causes double-strand breaks in chromosomal DNA. We further found that Vpr, an accessory gene product of HIV-1, is a major factor responsible for HIV-1–induced double-strand breaks. The purified Vpr protein promotes double-strand breaks when incubated with isolated nuclei, although it does not exhibit endonuclease activity in vitro. A carboxyl-terminally truncated Vpr mutant that is defective in DNA-binding activity is less capable of Vpr-dependent double-strand break formation in isolated nuclei. The data suggest that double-strand breaks induced by Vpr depend on its DNA-binding activity and that Vpr may recruit unknown nuclear factor(s) with positive endonuclease activity to chromosomal DNA. This is the first direct evidence that Vpr induces double-strand breaks in HIV-1–infected cells. We discuss the possible roles of Vpr-induced DNA damage in HIV-1 infection and the involvement of Vpr in further acquired immunodeficiency syndrome–related tumor development. (Cancer Res 2006; 66(2): 627-31)

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