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, S., Noorbakhsh, S., Stemkowski, P. L., Olechowski, C., Cohen, E. A., Ballanyi, K., Kerr, B., Pardo, C., Smith, P. A., Power, C. HIV‐1 viral protein R causes peripheral nervous system injury associated with in vivo neuropathic pain. FASEBJ . 24, 4343–4353 (2010). www.fasebj.org