title: Neurovirulence depends on virus input titer in brain in feline immunodeficiency virus infection: evidence for activation of innate immunity and neuronal injury.
abstract: Lentiruses cause neurological disease depending on the virus strain and its neurotropism, yet it remains uncertain to what the impact of infectious virus quantity in the brain early in infection is on the subsequent development of neurological disease or neurovirulence. We investigated the relationship between infectious virus input titer and the resulting neurovirulence, using ex vivo and in vivo assays of feline immunodeficiency virus (FIV)-induced neurovirulence. FIV infection of cell cultures and neonatal cats was performed using 10(2.5) (low-titer) or 10(4.5) (high-titer) 50% tissue culture infectious doses (TCID(50))/ml of the neurovirulent FIV strain, V1CSF. Ex vivo neurotoxicity assays revealed that conditioned medium (CM) from feline macrophages infected with high-titer (P <.001) or low-titer (P <.01) V1CSF induced greater neuronal death than CM from mock-infected cells. In vivo, animals infected intracranially with high-titer V1CSF showed neurodevelopmental delays compared to mock-infected animals (P <.001) and animals infected with low-titer V1CSF (P <.02), concurrent with reduced weight gains and greater depletion of CD4+ cells over a 12-week period. Neuropathological changes, including astrogliosis, macrophage activation, and neuronal damage, were evident in V1CSF-infected animals and were viral titer dependent. In vivo magnetic resonance (MR) spectroscopy and proton nuclear magnetic resonance ((1)H-NMR) spectroscopy of tissue extracts revealed evidence of neuronal injury, including reduced N-acetyl aspartate/creatine (P <.05) and increased trimethylamine/creatine (P <.05) ratios, in the frontal cortex of high-titer V1CSF-infected animals compared to the other groups. T2-weighted MR imaging detected increased signal intensities in the frontal cortex and white matter of V1CSF-infected animals relative to controls, which was more evident as viral titer increased (P <.01). The present findings indicate that lentivirus infectious titers in the brain during the early stages of infection determine the severity of neurovirulence, reflected by neurobehavioral deficits, together with neuroradiological and neuropathological findings of activation of innate immunity and neuronal injury.
authors.affiliation: Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
authors.forename: J B
authors.initials: JB
authors.lastname: Johnston
authors.forename: C
authors.initials: C
authors.lastname: Silva
authors.forename: T
authors.initials: T
authors.lastname: Hiebert
authors.forename: R
authors.initials: R
authors.lastname: Buist
authors.forename: M R
authors.initials: MR
authors.lastname: Dawood
authors.forename: J
authors.initials: J
authors.lastname: Peeling
authors.forename: C
authors.initials: C
authors.lastname: Power
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000032:analysis; D001921:Brain / Q000473:pathology / Q000821:virology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002415:Cats; D002478:Cells, Cultured; D002794:Choline / Q000032:analysis; D017077:Culture Media, Conditioned; D004195:Disease Models, Animal; D016181:Feline Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology; D005911:Gliosis; D007113:Immunity, Innate; D016089:Immunodeficiency Virus, Feline / Q000472:pathogenicity*; D008264:Macrophages / Q000821:virology; D009682:Magnetic Resonance Spectroscopy; D008744:Methylamines / Q000032:analysis; D009474:Neurons / Q000473:pathology; D014774:Virulence
chemical_list: D017077:Culture Media, Conditioned; D008744:Methylamines; D001224:Aspartic Acid; C000179:N-acetylaspartate; C023336:trimethylamine; D002794:Choline