Viral protein R of human immunodeficiency virus type-1 induces retrotransposition of long interspersed element-1
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RESEARCH
Open Access
Viral protein R of human immunodeficiency virus type-1 induces retrotransposition of long interspersed element-1 Kenta Iijima1†, Noriyuki Okudaira1,2,11†, Masato Tamura1, Akihiro Doi1,2, Yoshikazu Saito1, Mari Shimura1, Motohito Goto3, Akihiro Matsunaga1, Yuki I Kawamura4, Takeshi Otsubo4, Taeko Dohi4, Shigeki Hoshino1, Shigeyuki Kano2,5, Shotaro Hagiwara6, Junko Tanuma7, Hiroyuki Gatanaga7, Masanori Baba8, Taku Iguchi9,12, Motoko Yanagita9, Shinichi Oka7, Tadashi Okamura3,10 and Yukihito Ishizaka1*
Abstract Background: Viral protein R (Vpr), a protein of human immunodeficiency virus type-1 (HIV-1) with various biological functions, was shown to be present in the blood of HIV-1-positive patients. However, it remained unclear whether circulating Vpr in patients’ blood is biologically active. Here, we examined the activity of blood Vpr using an assay system by which retrotransposition of long interspersed element-1 (L1-RTP) was detected. We also investigated the in vivo effects of recombinant Vpr (rVpr) by administrating it to transgenic mice harboring human L1 as a transgene (hL1-Tg mice). Based on our data, we discuss the involvement of blood Vpr in the clinical symptoms of acquired immunodeficiency syndrome (AIDS). Results: We first discovered that rVpr was active in induction of L1-RTP. Biochemical analyses revealed that rVprinduced L1-RTP depended on the aryl hydrocarbon receptor, mitogen-activated protein kinases, and CCAAT/ enhancer-binding protein β. By using a sensitive L1-RTP assay system, we showed that 6 of the 15 blood samples from HIV-1 patients examined were positive for induction of L1-RTP. Of note, the L1-RTP-inducing activity was blocked by a monoclonal antibody specific for Vpr. Moreover, L1-RTP was reproducibly induced in various organs, including the kidney, when rVpr was administered to hL1-Tg mice. Conclusions: Blood Vpr is biologically active, suggesting that its monitoring is worthwhile for clarification of the roles of Vpr in the pathogenesis of AIDS. This is the first report to demonstrate a soluble factor in patients’ blood active for L1-RTP activity, and implies the involvement of L1-RTP in the development of human diseases. Keywords: HIV-1, Vpr, Blood, Retrotransposition, LINE-1, ORF1
Background Viral protein R (Vpr), an accessory gene of human immunodeficiency virus type-1 (HIV-1), encodes a virion-associated nuclear protein of ~15 kDa [1]. Vpr has a variety of biological functions, including cell cycle abnormalities at the G2/M phase and apoptosis of T cells and neuronal cells (for a recent review, see ref. [2]). Notably, it was shown that Vpr was present * Correspondence: [email protected] † Equal contributors 1 Department of Intractable Diseases, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan Full list of author information is available at the end of the article
in the blood of HIV-1-positive patients [3], and we previously reported that 20 of 52 blood samples from HIV-1-positive patien
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