HIV-1 viral protein R causes peripheral nervous system injury associated with in vivo neuropathic pain.
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.
Acharjee
Shaona
S
Department of Medicine,University of Alberta, Edmonton, AB, Canada.
Noorbakhsh
Farshid
F
Stemkowski
Patrick L
PL
Olechowski
Camille
C
Cohen
Eric A
EA
Ballanyi
Klaus
K
Kerr
Bradley
B
Pardo
Carlos
C
Smith
Peter A
PA
Power
Christopher
C
D000818:Animals; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000503:physiopathology / Q000821:virology; D005786:Gene Expression Regulation; D016336:Gene Products, vpr / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009437:Neuralgia / Q000150:complications*; D010523:Peripheral Nervous System Diseases / Q000150:complications* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020196:Trauma, Nervous System / Q000150:complications*
D016336:Gene Products, vpr