HIV-1 viral protein R causes peripheral nervous system injury associated with in vivo neuropathic pain.

Abstract

Painful peripheral neuropathy has become the principal neurological disorder in HIV/AIDS patients. Herein, we investigated the effects of a cytotoxic HIV-1 accessory protein, viral protein R (Vpr), on the peripheral nervous system (PNS). Host and viral gene expression was investigated in peripheral nerves from HIV-infected individuals and in HIV-infected human dorsal root ganglion (DRG) cultures by RT-PCR and immunocytochemistry. Cytosolic calcium ([Ca(2+)]) fluxes and neuronal membrane responses were analyzed in cultured DRGs. Neurobehavioral responses and cytokine levels were assessed in a transgenic mouse model in which the vpr transgene was expressed in an immunodeficient background (vpr/RAG1(-/-)). Vpr transcripts and proteins were detected in peripheral nerves and DRGs from HIV-infected patients. Exposure of rat or human cultured DRG neurons to Vpr rapidly increased [Ca(2+)] and action potential frequency while increasing input resistance. HIV infection of human DRG cultures caused neurite retraction (P<0.05), accompanied by induction of interferon-α (IFN-α) transcripts (P<0.05). vpr/RAG1(-/-) mice expressed Vpr together with increased IFN-α (P<0.05) in the PNS and also exhibited mechanical allodynia, unlike their vpr/RAG1(-/-) littermates (P<0.05). Herein, Vpr caused DRG neuronal damage, likely through cytosolic calcium activation and cytokine perturbation, highlighting Vpr's contribution to HIV-associated peripheral neuropathy and ensuing neuropathic pain.

• Authors: Shaona Acharjee, Farshid Noorbakhsh, Patrick L Stemkowski, Camille Olechowski, Eric A Cohen, Klaus Ballanyi, Bradley Kerr, Carlos Pardo, Peter A Smith, Christopher Power
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 24 Issue 11 Pg. 4343-53 (Nov 2010) ISSN: 1530-6860 [Electronic] United States
• PMID: 20628092 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Gene Products, vpr

Topics

• Animals
• Cells, Cultured
• Ganglia, Spinal (physiopathology, virology)
• Gene Expression Regulation
• Gene Products, vpr (genetics, metabolism)
• HIV-1
• Humans
• Immunohistochemistry
• Male
• Mice
• Mice, Transgenic
• Neuralgia (complications)
• Peripheral Nervous System Diseases (complications, physiopathology)
• Rats
• Rats, Sprague-Dawley
• Reverse Transcriptase Polymerase Chain Reaction
• Trauma, Nervous System (complications)