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Journal of Virology, March 2008, p. 2528-2542, Vol. 82, No. 5
0022-538X/08/$08.00+0     doi:10.1128/JVI.02094-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Vpr Inhibits Axonal Outgrowth through Induction of Mitochondrial Dysfunction{triangledown}

Hiroko Kitayama,1 Yoshiharu Miura,1 Yoshinori Ando,1 Shigeki Hoshino,2,3 Yukihito Ishizaka,2 and Yoshio Koyanagi1*

Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan,1 Department of Intractable Diseases, International Medical Center of Japan, Tokyo 162-8655, Japan,2 Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba 305-8577, Japan3

Received 21 September 2007/ Accepted 12 December 2007

Human immunodeficiency virus type 1 (HIV-1)-infected macrophages damage mature neurons in the brain, although their effect on neuronal development has not been clarified. In this study, we show that HIV-1-infected macrophages produce factors that impair the development of neuronal precursor cells and that soluble viral protein R (Vpr) is one of the factors that has the ability to suppress axonal growth. Cell biological analysis revealed that extracellularly administered recombinant Vpr (rVpr) clearly accumulated in mitochondria where a Vpr-binding protein adenine nucleotide translocator localizes and also decreased the mitochondrial membrane potential, which led to ATP synthesis. The depletion of ATP synthesis reduced the transportation of mitochondria within neurites. This mitochondrial dysfunction inhibited axonal growth even when the frequency of apoptosis was not significant. We also found that point mutations of arginine (R) residues to alanine (A) residues at positions 73, 77, and 80 rendered rVpr incapable of causing mitochondrial membrane depolarization and axonal growth inhibition. Moreover, the Vpr-induced inhibition was suppressed after treatment with a ubiquinone analogue (ubiquinone-10). Our results suggest that soluble Vpr is a major viral factor that causes a disturbance in neuronal development through the induction of mitochondrial dysfunction. Since ubiquinone-10 protects the neuronal plasticity in vitro, it may be a therapeutic agent that can offer defense against HIV-1-associated neurological disease.

* Corresponding author. Mailing address: Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, 53 Shogoinkawara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Phone: 81-75-751-4811. Fax: 81-75-751-4812. E-mail: ykoyanag{at}virus.kyoto-u.ac.jp

{triangledown} Published ahead of print on 19 December 2007.

Journal of Virology, March 2008, p. 2528-2542, Vol. 82, No. 5
0022-538X/08/$08.00+0     doi:10.1128/JVI.02094-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Romani, B., Engelbrecht, S. (2009). Human immunodeficiency virus type 1 Vpr: functions and molecular interactions. J. Gen. Virol. 90: 1795-1805 [Abstract] [Full Text]  


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