Lentiviral Neuropathogenesis: Comparative Neuroinvasion, Neurotropism, Neurovirulence, and Host Neurosusceptibility

Patrick, Megan K.; Johnston, James B.; Power, Christopher

doi:10.1128/jvi.76.16.7923-7931.2002

Cited by 51 publications

(30 citation statements)

References 120 publications

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“…Indeed, Schwann cells may also be targets for cytotoxins released by FIV-infected or activated macrophages, consistent with reports of HIV infection of the CNS in which astrocyte apoptosis is correlated with the development of HIV-associated dementia and neuronal loss (52). However, Schwann cells did not exhibit productive FIV infection, similar to neurons, which are also not infected by FIV (53). It is also plausible that sensory perikaryal dysfunction in FIV-infected animals results in failure to elaborate and export structural proteins in nerve including neurofilament and tubulin that are required to maintain axon caliber and integrity, manifesting as neurite retraction in the present studies.…”

Section: Discussionsupporting

confidence: 65%

Lentivirus Infection Causes Neuroinflammation and Neuronal Injury in Dorsal Root Ganglia: Pathogenic Effects of STAT-1 and Inducible Nitric Oxide Synthase

Zhu

Jones

Tsutsui

et al. 2005

The Journal of Immunology

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Distal sensory polyneuropathy (DSP) is currently the most common neurological complication of HIV infection in the developed world and is characterized by sensory neuronal injury accompanied by inflammation, which is clinically manifested as disabling pain and gait instability. We previously showed that feline immunodeficiency virus (FIV) infection of cats caused DSP together with immunosuppression in cats, similar to that observed in HIV-infected humans. In this study, we investigated the pathogenic mechanisms underlying the development of FIV-induced DSP using feline dorsal root ganglia (DRG) cultures, consisting of neurons, Schwann cells, and macrophages. FIV-infected cultures exhibited viral Ags (p24 and envelope) in macrophages accompanied by neuronal injury, indicated by neurite retraction, neuronal loss and decreased soma size, compared with mock-infected (control) cultures. FIV infection up-regulated inducible NO synthase (iNOS), STAT-1, and TNF-α mRNA levels in DRG cultures. Increased STAT-1 and iNOS mRNA levels were also observed in DRGs from FIV-infected animals relative to mock-infected controls. Similarly, immunolabeling studies of DRGs from FIV-infected animals showed that macrophages were the principal sources of STAT-1 and iNOS protein production. The iNOS inhibitor aminoguanidine reduced nitrotyrosine and protein carbonyl levels, together with preventing neuronal injury in FIV-infected DRG cultures. The present studies indicate that FIV infection of DRGs directly contributes to axonal and neuronal injury through a mechanism involving macrophage immune activation, which is mediated by STAT-1 and iNOS activation.

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Section: Discussionsupporting

confidence: 65%

Lentivirus Infection Causes Neuroinflammation and Neuronal Injury in Dorsal Root Ganglia: Pathogenic Effects of STAT-1 and Inducible Nitric Oxide Synthase

Zhu

Jones

Tsutsui

et al. 2005

The Journal of Immunology

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“…A signature feature of lentivirus infections, including human (HIV), simian (SIV), and feline (FIV) immunodeficiency viruses, is that they cause neurological disease, likely because of infection of the nervous system coupled with progressive immunosuppression (Patrick et al, 2002). Although the spectrum of neurological disease phenotypes associated with HIV infection is broad and growing, the principal neurobehavioral phenotypes in animal lentivirus infections remain mostly analyzed using qualitative assays.…”

Section: Introductionmentioning

confidence: 99%

Neurobehavioral Performance in Feline Immunodeficiency Virus Infection: Integrated Analysis of Viral Burden, Neuroinflammation, and Neuronal Injury in Cortex

Maingat

Vivithanaporn²,

Zhu³

et al. 2009

Journal of Neuroscience

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Human immunodeficiency virus (HIV) infection causes motor and neurocognitive abnormalities affecting Ͼ50% of children and 20% of adults with HIV/AIDS (acquired immunodeficiency syndrome). The closely related lentivirus, feline immunodeficiency virus (FIV), also causes neurobehavioral deficits. Herein, we investigated the extent to which FIV infection affected specific motor and cognitive tasks in conjunction with viral burden and immune responses within the brain. Neonatal animals were infected with a neurovirulent FIV strain (FIV-Ch) and assessed in terms of systemic immune parameters, viral burden, neurobehavioral performance, and neuropathological features. FIV-infected animals displayed less weight gain and lower blood CD4 ϩ T-cell levels than mock-infected animals ( p Ͻ 0.05). Gait analyses disclosed greater gait width with increased variation in FIV-infected animals ( p Ͻ 0.05). Maze performance showed that FIV-infected animals were slower and made more navigational errors than mock-infected animals ( p Ͻ 0.05). In the object memory test, the FIV-infected group exhibited fewer successful steps with more trajectory errors compared with the mock-infected group ( p Ͻ 0.05). Performance on the gait, maze, and object memory tests was inversely correlated with F4/80 and CD3 expression ( p Ͻ 0.05) and with viral burden in parietal cortex ( p Ͻ 0.05). Amino acid analysis in cortex showed that D-serine levels were reduced in FIV-infected animals, which was accompanied by diminished kainate and AMPA receptor subunit expression ( p Ͻ 0.05). The neurobehavioral findings in FIV-infected animals were associated with increased gliosis and reduced cortical neuronal counts ( p Ͻ 0.05). The present studies indicated that specific motor and neurocognitive abilities were impaired in FIV infection and that these effects were closely coupled with viral burden, neuroinflammation, and neuronal loss.

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“…Of importance, MMP-2 is induced in macrophages after HIV-1 infection and was associated with the development of HIV-induced neurodegeneration (19). In fact, activation and proliferation of monocytoid cells in the brain is assumed to be a key determinant of HIV neuropathogenesis (20). The proteolytic product, SDF(5-67), shows no chemotactic properties but acquired selective neurotoxic effects (18).…”

mentioning

confidence: 99%

Proteolytic processing of SDF-1α reveals a change in receptor specificity mediating HIV-associated neurodegeneration

Vergote

Butler

Ooms

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Proteolytic cleavage of constitutively expressed proteins can generate peptides with novel bioactive properties. Matrix metalloproteinase (MMP)-2 cleaves the 4 amino-terminal residues of the chemokine, stromal cell-derived factor (SDF)-1␣, yielding a highly neurotoxic molecule, SDF(5-67), which fails to bind to its cognate receptor, CXCR4. Herein, we detected SDF(5-67) in brain monocytoid cells of HIV-infected persons, particularly in those with HIV-associated dementia. SDF(5-67) activated cell type-specific expression of proinflammatory genes including IL-1␤, TNF␣, indoleamine 2,3-dioxygenase (IDO), and IL-10 in both astrocytic and monocytoid cells (P < 0.05). Unlike SDF-1␣, SDF(5-67) caused neuronal membrane perturbations with ensuing neurotoxicity and apoptosis (P < 0.05) through engagement of an inducible receptor. CXCR3 antagonists and siRNA-mediated knockdown of CXCR3 inhibited SDF(5-67)-stimulated neurophysiological changes, neuronal death, and neuroimmune activation (P < 0.05). Moreover SDF(5-67) bound directly to CXCR3 in a competitive manner, mediated by its amino terminus. In vivo neuroinflammation, neuronal loss, and neurobehavioral abnormalities caused by SDF(5-67) (P < 0.05) were prevented by a CXCR3 antagonist. These studies reveal additive neuropathogenic properties exerted by a proteolytically cleaved chemokine as consequences of a change in receptor specificity, culminating in neurodegeneration.apoptosis ͉ chemokine ͉ human immunodeficiency virus ͉ neuron ͉ stromal cell-derived factor-1␣

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Lentiviral Neuropathogenesis: Comparative Neuroinvasion, Neurotropism, Neurovirulence, and Host Neurosusceptibility

Cited by 51 publications

References 120 publications

Lentivirus Infection Causes Neuroinflammation and Neuronal Injury in Dorsal Root Ganglia: Pathogenic Effects of STAT-1 and Inducible Nitric Oxide Synthase

Lentivirus Infection Causes Neuroinflammation and Neuronal Injury in Dorsal Root Ganglia: Pathogenic Effects of STAT-1 and Inducible Nitric Oxide Synthase

Neurobehavioral Performance in Feline Immunodeficiency Virus Infection: Integrated Analysis of Viral Burden, Neuroinflammation, and Neuronal Injury in Cortex

Proteolytic processing of SDF-1α reveals a change in receptor specificity mediating HIV-associated neurodegeneration

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