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HIV-associated neurocognitive disorders (HAND) represent a constellation of neurological disabilities defined by neuropsychological impairments, neurobehavioral abnormalities and motor deficits. To gain insights into the mechanisms underlying the development of these disabilities, several transgenic models have been developed over the past two decades, which have provided important information regarding the cellular and molecular factors contributing to the neuropathogenesis of HAND. Herein, we concentrate on the neuropathogenic effects of HIV-1 Vpr expressed under the control of c-fms, resulting transgene expression in myeloid cells in both the central and peripheral nervous systems. Vpr's actions, possibly through its impact on cell cycle machinery, in brain culminate in neuronal and astrocyte injury and death through apoptosis involving activation of caspases-3, -6 and -9 depending on the individual target cell type. Indeed, these outcomes are also induced by soluble Vpr implying Vpr's effects stem from direct interaction with target cells. Remarkably, in vivo transgenic Vpr expression induces a neurodegenerative phenotype defined by neurobehavioral deficits and neuronal loss in the absence of frank inflammation. Implantation of another viral protein, hepatitis C virus (HCV) core, into Vpr transgenic animals' brains stimulated neuroinflammation and amplified the neurodegenerative disease phenotype, thereby recapitulating HCV's putative neuropathogenic actions. The availability of different transgenic models to study HIV neuropathogenesis represents exciting and innovative approaches to understanding disease mechanisms and perhaps developing new therapeutic strategies in the future.

Background: Viral diversity and abundance are defining properties of human immunodeficiency virus (HIV)-1's biology and pathogenicity. Despite the increasing availability of antiretroviral therapy, HIV-associated dementia (HAD) continues to be a devastating consequence of HIV-1 infection of the brain although the underlying disease mechanisms remain uncertain. Herein, molecular diversity within the HIV-1 non-structural gene, Vpr, was examined in RNA sequences derived from brain and blood of HIV/AIDS patients with or without HIV-associated dementia (HAD) together with the ensuing pathobiological effects., Results: Cloned brain- and blood-derived full length vpr alleles revealed that amino acid residue 77 within the brain-derived alleles distinguished HAD (77Q) from non-demented (ND) HIV/AIDS patients (77R) (p < 0.05) although vpr transcripts were more frequently detected in HAD brains (p < 0.05). Full length HIV-1 clones encoding the 77R-ND residue induced higher IFN-α, MX1 and BST-2 transcript levels in human glia relative to the 77Q-HAD encoding virus (p < 0.05) but both viruses exhibited similar levels of gene expression and replication. Myeloid cells transfected with 77Q-(pVpr77Q-HAD), 77R (pVpr77R-ND) or Vpr null (pVpr(-))-containing vectors showed that the pVpr77R-ND vector induced higher levels of immune gene expression (p < 0.05) and increased neurotoxicity (p < 0.05). Vpr peptides (amino acids 70-96) containing the 77Q-HAD or 77R-ND motifs induced similar levels of cytosolic calcium activation when exposed to human neurons. Human glia exposed to the 77R-ND peptide activated higher transcript levels of IFN-α, MX1, PRKRA and BST-2 relative to 77Q-HAD peptide (p < 0.05). The Vpr 77R-ND peptide was also more neurotoxic in a concentration-dependent manner when exposed to human neurons (p < 0.05). Stereotaxic implantation of full length Vpr, 77Q-HAD or 77R-ND peptides into the basal ganglia of mice revealed that full length Vpr and the 77R-ND peptide caused greater neurobehavioral deficits and neuronal injury compared with 77Q-HAD peptide-implanted animals (p < 0.05)., Conclusions: These observations underscored the potent neuropathogenic properties of Vpr but also indicated viral diversity modulates innate neuroimmunity and neurodegeneration.

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.