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|Title:||Interactions between human immunodeficiency virus (HIV)-1 Vpr expression and innate immunity influence neurovirulence|
Carlos A. Pardo
Éric A. Cohen
University of Alberta
University of Calgary
The Johns Hopkins School of Medicine
Institut de Recherches Cliniques de Montreal
|Keywords:||Immunology and Microbiology;Medicine|
|Citation:||Retrovirology. Vol.8, (2011)|
|Abstract:||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. © 2011 Na et al; licensee BioMed Central Ltd.|
|Appears in Collections:||Scopus 2011-2015|
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