Interactions between human immunodeficiency virus (HIV)-1 Vpr expression and innate immunity influence neurovirulence

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>Cloned brain- and blood-derived full length <it>vpr </it>alleles revealed that amino acid residue 77 within the brain-derived alleles distinguished HAD (77Q) from non-demented (ND) HIV/AIDS patients (77R) (<it>p </it>< 0.05) although <it>vpr </it>transcripts were more frequently detected in HAD brains (<it>p </it>< 0.05). Full length HIV-1 clones encoding the 77R-ND residue induced higher <it>IFN-α</it>, <it>MX1 </it>and <it>BST-2 </it>transcript levels in human glia relative to the 77Q-HAD encoding virus (<it>p </it>< 0.05) but both viruses exhibited similar levels of gene expression and replication. Myeloid cells transfected with 77Q-(p<it>Vpr77Q-HAD</it>), 77R (p<it>Vpr77R-ND</it>) or Vpr null (p<it>Vpr</it>^<it>(-)</it>)-containing vectors showed that the p<it>Vpr77R-ND </it>vector induced higher levels of immune gene expression (<it>p </it>< 0.05) and increased neurotoxicity (<it>p </it>< 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 <it>IFN-α</it>, <it>MX1</it>, <it>PRKRA </it>and <it>BST-2 </it>relative to 77Q-HAD peptide (<it>p </it>< 0.05). The Vpr 77R-ND peptide was also more neurotoxic in a concentration-dependent manner when exposed to human neurons (<it>p </it>< 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 (<it>p </it>< 0.05).</p> <p>Conclusions</p> <p>These observations underscored the potent neuropathogenic properties of Vpr but also indicated viral diversity modulates innate neuroimmunity and neurodegeneration.</p

Unexpected Microglial “De-activation” Associated With Altered Synaptic Transmission in the Early Stages of an Animal Model of Multiple Sclerosis

Multiple sclerosis, and its animal model—experimental autoimmune encephalomyelitis (EAE), is a demyelinating disease causing motor and sensory dysfunction, as well as behavioral comorbidities. In exploring possible functional changes underlying behavioral comorbidities in EAE, we observed increased excitatory drive onto the major cells of the basolateral amygdala. This was associated with increased numbers of dendritic spines. An unexpected finding was that microglial cells at this time were in a “deactivated” state, and further studies suggested that the microglial deactivation was responsible for the increased excitatory drive. This is the first report of microglial deactivation in an inflammatory disease and raises many questions as to the underlying mechanisms and functional relevance

Early Life Inflammation Increases CA1 Pyramidal Neuron Excitability in a Sex and Age Dependent Manner through a Chloride Homeostasis Disruption

Early life, systemic inflammation causes long-lasting changes in behavior. To unmask possible mechanisms associated with this phenomenon, we asked whether the intrinsic membrane properties in hippocampal neurons were altered as a consequence of early life inflammation. C57BL/6 mice were bred in-house and both male and female pups from multiple litters were injected with lipopolysaccharide (LPS; 100 &mu;g/kg, i.p.) or vehicle at postnatal day (P)14, and kept until adolescence (P35&ndash;P45) or adulthood (P60&ndash;P70), when brain slices were prepared for whole-cell and perforated-patch recordings from CA1 hippocampal pyramidal neurons. In neurons of adult male mice pretreated with LPS, the number of action potentials elicited by depolarizing current pulses was significantly increased compared with control neurons, concomitant with increased input resistance, and a lower action potential threshold. Although these changes were not associated with changes in relevant sodium channel expression or differences in capacitance or dendritic architecture, they were linked to a mechanism involving intracellular chloride overload, revealed through a depolarized GABA reversal potential and increased expression of the chloride transporter, NKCC1. In contrast, no significant changes were observed in neurons of adult female mice pretreated with LPS, nor in adolescent mice of either sex. These data uncover a potential mechanism involving neonatal inflammation-induced plasticity in chloride homeostasis, which may contribute to early life inflammation-induced behavioral alterations

Inflammation and epithelial cell injury in AIDS enteropathy: involvement of endoplasmic reticulum stress

Immunosuppressive lentivirus infections, including human, simian, and feline immunodeficiency viruses (HIV, SIV, and FIV, respectively), cause the acquired immunodeficiency syndrome (AIDS), frequently associated with AIDS enteropathy. Herein, we investigated the extent to which lentivirus infections affected mucosal integrity and intestinal permeability in conjunction with immune responses and activation of endoplasmic reticulum (ER) stress pathways. Duodenal biopsies from individuals with HIV/AIDS exhibited induction of IL-1β, CD3ε, HLA-DRA, spliced XBP-1(Xbp-1s), and CHOP expression compared to uninfected persons (P<0.05). Gut epithelial cells exposed to HIV-1 Vpr demonstrated elevated TNF-α, IL-1β, spliced Xbp-1s, and CHOP expression (P<0.05) together with calcium activation and disruption of epithelial cell monolayer permeability. In addition to reduced blood CD4+ T lymphocyte levels, viral loads in the gut and plasma were high in FIV-infected animals (P<0.05). FIV-infected animals also exhibited a failure to gain weight and increased lactulose/mannitol ratios compared with uninfected animals (P<0.05). Proinflammatory and ER stress gene expression were activated in the ileum of FIV-infected animals (P<0.05), accompanied by intestinal epithelial damage with loss of epithelial cells and leukocyte infiltration of the lamina propria. Lentivirus infections cause gut inflammation and ensuing damage to intestinal epithelial cells, likely through induction of ER stress pathways, resulting in disruption of gut functional integrity.—Maingat, F., Halloran, B., Acharjee, S., van Marle, G., Church, D., Gill, M. J., Uwiera, R. R. E., Cohen, E. A., Meddings, J., Madsen, K., Power, C. Inflammation and epithelial cell injury in AIDS enteropathy: involvement of endoplasmic reticulum stress