Abstract
BackgroundViral 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.ResultsCloned 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).ConclusionsThese observations underscored the potent neuropathogenic properties of Vpr but also indicated viral diversity modulates innate neuroimmunity and neurodegeneration.
Highlights
Viral diversity and abundance are defining properties of human immunodeficiency virus (HIV)-1’s biology and pathogenicity
Brain-derived Human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) sequences exhibited a consistent mutation, which distinguished non-demented (ND) from demented (HAD) HIV/acquired immunodeficiency syndrome (AIDS) patients; the molecular motif within Vpr associated with dementia was less neuropathogenic and exerted blunted antiviral and neurotoxic host responses, providing a new perspective into HIV-associated neurovirulence
HIV-1 vpr sequence diversity in brain and blood Previous studies indicated both Vpr-encoding transcripts and proteins were present in the brains of HIV-infected persons [20,33], in cells of monocytoid lineage in keeping with other studies of HIV neurotropism [34,35]
Summary
Viral diversity and abundance are defining properties of human immunodeficiency virus (HIV)-1’s biology and pathogenicity. Among blood-derived HIV sequences, Vpr exhibits molecular diversity the mechanistic consequences of these sequence differences are unclear but appear to be associated with clinical phenotypes in some circumstances [26,27,28,29]. Given these circumstances including Vpr expression and potential pathogenic actions in the brain together with its capacity to mutate in conjunction with clinical phenotypes, it was hypothesized that Vpr might show molecular diversity in the brain, influencing its functions as a neurotoxic ligand or a pathogenic modulator of neuroinflammation [30,31,32]. Brain-derived HIV-1 Vpr sequences exhibited a consistent mutation, which distinguished non-demented (ND) from demented (HAD) HIV/AIDS patients; the molecular motif within Vpr associated with dementia was less neuropathogenic and exerted blunted antiviral and neurotoxic host responses, providing a new perspective into HIV-associated neurovirulence
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