Tumor necrosis factor-α and virus expression in the central nervous system of cats infected with feline immunodeficiency virus

Poli, Alessandro; Pistello, Mauro; Carli, Maria Antonietta; Abramo, Francesca; Mancuso, G; Nicoletti, Elisa; Bendinelli, Mauro

doi:10.3109/13550289909045375

Cited by 32 publications

(28 citation statements)

References 30 publications

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“…Previous studies have shown that glial activation and neuronal injury are cardinal features of lentivirus infections (40)(41)(42). To define the effects of repeated LPS exposures in terms of the neuropathologic changes, brain sections from each experimental group were assessed, revealing limited Iba-1 immunoreactivity in microglia-like cells on PBS-exposed (Fig.…”

Section: Neuropathologic and Neurobehavioral Effects Of Lps Exposurementioning

confidence: 99%

Regulation of Lentivirus Neurovirulence by Lipopolysaccharide Conditioning: Suppression of CXCL10 in the Brain by IL-10

Maingat

Viappiani

Zhu

et al. 2009

The Journal of Immunology

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Lentivirus infections including HIV and feline immunodeficiency virus (FIV) cause neurovirulence, which is largely mediated by innate immunity. To investigate the interactions between neurovirulence and repeated conditioning by innate immune activation, models of lentivirus infection were exposed to LPS. Gene expression in HIV-infected (HIV+) and control (HIV−) patient brains was compared by real time RT-PCR and immunocytochemistry. Supernatants from mock and HIV-infected monocyte-derived macrophages exposed to LPS were applied to human neurons. FIV-infected (FIV+) and control (FIV−) animals were exposed repeatedly to LPS postinfection together with concurrent neurobehavioral testing, viral load, and host gene analyses. Brains from HIV+ individuals exhibited induction of CD3ε, CXCL10, and granzyme A expression (p < 0.05). Supernatants from HIV+ monocyte-derived macrophages induced CXCL10 expression in neurons, which was diminished by IL-10 treatment (p < 0.05). LPS-exposed FIV+ animals demonstrated lower plasma and brain viral loads (p < 0.05). Neuronal CXCL10 expression was increased in FIV+ animals but was suppressed by LPS exposure, together with reduced brain CD3ε and granzyme A expression (p < 0.05). In conjunction with preserved NeuN-positive neuronal counts in parietal cortex (p < 0.05), FIV+ animals exposed to LPS also showed less severe neurobehavioral deficits (p < 0.05). Repeated LPS exposures suppressed CXCL10 in the brain and ensuing T cell infiltration with a concomitant reduction in neurovirulence. Thus, innate immune chronic conditioning exerted beneficial effects on neurovirulence through suppression of a specific chemotactic factor, CXCL10, mediated by IL-10, leading to reduced leukocyte infiltration and release of neurotoxic factors.

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Section: Neuropathologic and Neurobehavioral Effects Of Lps Exposurementioning

confidence: 99%

Regulation of Lentivirus Neurovirulence by Lipopolysaccharide Conditioning: Suppression of CXCL10 in the Brain by IL-10

Maingat

Viappiani

Zhu

et al. 2009

The Journal of Immunology

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“…Neuropathogenic effects mediated by FIV infection are viral strain specific (Power et al, 1998; and vary from seizures, ataxia, psychomotor retardation, aggressivity, disrupted sleep and arousal patterns to stereotypic motor behaviors (Phillips et al, 1994;Prospéro-García et al, 1999;Steigerwald et al, 1999). As with HIV and SIV infections, neuroimmune activation occurs in FIV, including microglial and astrocytic activation, leukocyte infiltration with the ensuing production of cytokines, chemokines, proteases, and other inflammatory factors in the CNS (Power et al, 1997;Poli et al, 1999;Noorbakhsh et al, 2006). These neuroinflammatory changes are accompanied by neuronal injury and loss in the brain, especially in the basal ganglia and cortical regions, which are the major sites of infection and immune activation (Zink et al, 2006;Fletcher et al, 2008).…”

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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“…Recently, elevated expression of MMPs in the CNS following lentivirus infection has suggested a role for these enzymes in lentiviral neuropathogenesis (3,9,63), possibly through their ability to promote breakdown in blood-brain barrier (BBB) integrity and cell death (59,75). Numerous factors that regulate MMP transcription are also elevated during lentivirus infection of the CNS, such as the cytokines tumor necrosis factor alpha (TNF-␣) (50,71) and alpha interferon (IFN-␣) (28,57) and the ␤-chemokines RANTES and MIP-1␣ (60). Induction of several MMPs by mediators of inflammation or viral proteins involves activation of specific transcription factors, such as AP-1 and NF-B (4,30).…”

mentioning

confidence: 99%

Lentivirus Infection in the Brain Induces Matrix Metalloproteinase Expression: Role of Envelope Diversity

Johnston

Jiang

Marle

et al. 2000

J Virol

107

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Infection of the brain by lentiviruses, including human immunodeficiency virus (HIV) and feline immunodeficiency virus (FIV), causes inflammation and results in neurodegeneration. Molecular diversity within the lentivirus envelope gene has been implicated in the regulation of cell tropism and the host response to infection. Here, we examine the hypothesis that envelope sequence diversity modulates the expression of host molecules implicated in lentivirus-induced brain disease, including matrix metalloproteinases (MMP) and related transcription factors. Infection of primary macrophages by chimeric HIV clones containing brainderived envelope fragments from patients with HIV-associated dementia (HAD) or nondemented AIDS patients (HIV-ND) showed that MMP-2 and -9 levels in conditioned media were significantly higher for the HAD clones. Similarly, STAT-1 and JAK-1 levels were higher in macrophages infected by HAD clones. Infections of primary feline macrophages by the neurovirulent FIV strain (V 1 CSF), the less neurovirulent strain (Petaluma), and a chimera containing the V 1 CSF envelope in a Petaluma background (FIV-Ch) revealed that MMP-2 and -9 levels were significantly higher in conditioned media from V 1 CSF-and FIV-Ch-infected macrophages, which was associated with increased intracellular STAT-1 and JAK-1 levels. The STAT-1 inhibitor fludarabine significantly reduced MMP-2 expression, but not MMP-9 expression, in FIV-infected macrophages. Analysis of MMP mRNA and protein levels in brain samples from HIV-infected persons or FIV-infected cats showed that MMP-2 and -9 levels were significantly increased in lentivirus-infected brains compared to those of uninfected controls. Elevated MMP expression was accompanied by significant increases in STAT-1 and JAK-1 mRNA and protein levels in the same brain samples. The present findings indicate that two lentiviruses, HIV and FIV, have common mechanisms of MMP-2 and -9 induction, which is modulated in part by envelope sequence diversity and the STAT-1/JAK-1 signaling pathway.

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Tumor necrosis factor-α and virus expression in the central nervous system of cats infected with feline immunodeficiency virus

Cited by 32 publications

References 30 publications

Regulation of Lentivirus Neurovirulence by Lipopolysaccharide Conditioning: Suppression of CXCL10 in the Brain by IL-10

Regulation of Lentivirus Neurovirulence by Lipopolysaccharide Conditioning: Suppression of CXCL10 in the Brain by IL-10

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

Lentivirus Infection in the Brain Induces Matrix Metalloproteinase Expression: Role of Envelope Diversity

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