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Human immunodeficiency virus type 1 Vpr inhibits axonal outgrowth through induction of mitochondrial dysfunction
Hiroko Kitayama1, Yoshiharu Miura, Yoshinori Ando
1Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, 53 Shogoinkawara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Abstract:
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.
Insights
Human immunodeficiency virus type 1 (HIV-1) infection impairs neuronal development. Soluble viral protein R (Vpr) disrupts mitochondrial function, inhibiting axonal growth and suggesting ubiquinone-10 as a potential therapeutic agent.
Area of Science:
- Neuroscience
- Virology
- Cell Biology
Background:
- Human immunodeficiency virus type 1 (HIV-1)-infected macrophages are known to damage mature neurons.
- The specific impact of HIV-1 on the developmental processes of neurons remains unclear.
Purpose of the Study:
- To investigate how HIV-1-infected macrophages affect neuronal precursor cell development.
- To identify specific viral factors responsible for inhibiting neuronal development, particularly axonal growth.
Main Methods:
- Cell biological analysis of extracellularly administered recombinant Vpr (rVpr) in neuronal precursor cells.
- Assessment of mitochondrial function, including membrane potential and ATP synthesis.
- Investigation of the role of specific Vpr mutations (R73A, R77A, R80A) in mitochondrial dysfunction and axonal growth inhibition.
- Evaluation of the protective effect of ubiquinone-10 against Vpr-induced neurotoxicity.
Main Results:
- HIV-1-infected macrophages produce factors that inhibit neuronal precursor cell development.
- Soluble viral protein R (Vpr) was identified as a key factor suppressing axonal growth.
- Recombinant Vpr accumulated in mitochondria, decreased mitochondrial membrane potential, and impaired ATP synthesis.
- Mitochondrial dysfunction led to reduced mitochondrial transport in neurites, inhibiting axonal growth independently of apoptosis.
- Specific Vpr mutations abolished mitochondrial depolarization and axonal growth inhibition.
- Ubiquinone-10 treatment suppressed Vpr-induced inhibition of axonal growth.
Conclusions:
- Soluble Vpr is a significant viral factor contributing to neuronal development disturbances via mitochondrial dysfunction.
- Mitochondrial dysfunction induced by Vpr disrupts axonal growth in developing neurons.
- Ubiquinone-10 demonstrates neuroprotective properties in vitro and may serve as a therapeutic agent against HIV-1-associated neurological disorders.
