Abstract
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.
Highlights
A high incidence of malignant tumors, such as non-Hodgkin’s lymphoma, Kaposi’s sarcoma, and invasive cervical cancer [acquired immunodeficiency syndrome (AIDS)–defining cancers], is epidemiologically associated with HIV-1 infection [1, 2]
We found that HIV-1 infection induces double-strand breaks of chromosomal DNA, as detected using pulsed-field gel electrophoresis (PFGE)
HT1080 cells were infected with HIV-1 that had 200 ng/mL of p24 Gag antigen, giving a multiplicity of infection (MOI) of 0.7, and the cellular DNA was fractionated using PFGE
Summary
A high incidence of malignant tumors, such as non-Hodgkin’s lymphoma, Kaposi’s sarcoma, and invasive cervical cancer [acquired immunodeficiency syndrome (AIDS)–defining cancers], is epidemiologically associated with HIV-1 infection [1, 2]. These neoplasms are attributable mainly to diseases that accompany immunodeficiency, including coinfection with EBV, human herpes virus 8, and human papillomavirus [1, 2]. In addition to these AIDS-defining cancers, several non-AIDS-defining cancers occur with a higher incidence in HIV-infected individuals [3, 4]. It has been reported that HIV-1 infection induces DNA damage responses by activating Rad3-related or ataxia-telangiectasia mutated proteins and pro-
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