Acute SIV infection of the brain leads to upregulation of IL6 and interferon-regulated genes: expression patterns throughout disease progression and impact on neuroAIDS

Roberts, Eleanor; Burudi, E.M.E.; Flynn, Claudia T.; Madden, Lisa J.; Roinick, Kelli L.; Watry, Debbie D.; Zandonatti, Michelle; Taffe, Michael A.; Fox, Howard S.

doi:10.1016/j.jneuroim.2004.08.030

Cited by 75 publications

(73 citation statements)

References 62 publications

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“…The early presence of antiviral CTLs in the brain likely contributes to a relatively low viral load in the brain, as suggested by our findings of a significant decline in viral RNA between 2 and 11 wk after SIV inoculation in rhesus monkeys (40) and the effects of early CD8 depletion, which lead to high brain viral RNA levels and early death (41,42). Although we did not examine the possibility of latency, the role of the adaptive, as opposed to the innate, immune contribution to latency in the brain (43) is of interest for future studies.…”

Section: Discussionmentioning

confidence: 54%

Enrichment and Persistence of Virus-Specific CTL in the Brain of Simian Immunodeficiency Virus-Infected Monkeys Is Associated with a Unique Cytokine Environment

Marcondes

Burdo

Sopper

et al. 2007

The Journal of Immunology

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The host reaction to infection of the brain contributes to a number of CNS pathologies including neuro-AIDS. In this study, we have identified the accumulation of SIV-specific CTL in the brains of SIV-infected animals who have neurophysiological abnormalities but are otherwise asymptomatic. SIV-specific CTL enter the brain early after viral infection and are maintained in the brain even when those reactive with an immunodominant epitope in Tat are lost from the rest of the body. The specialized CNS environment contributes to this unique outcome. Following SIV infection, brain levels of IL-15 were significantly elevated whereas IL-2 was absent, creating an environment that favors CTL persistence. Furthermore, in response to IL-15, brain-derived CD8+ T cells could expand in greater numbers than those from spleen. The accumulation, persistence, and maintenance of CTL in the brain are closely linked to the increased levels of IL-15 in the absence of IL-2 in the CNS following SIV infection.

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Section: Discussionmentioning

confidence: 54%

Enrichment and Persistence of Virus-Specific CTL in the Brain of Simian Immunodeficiency Virus-Infected Monkeys Is Associated with a Unique Cytokine Environment

Marcondes

Burdo

Sopper

et al. 2007

The Journal of Immunology

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“…However, viral load is under detection limit and the putamen of these asymptomatic animals with impaired dopamine neurotransmission is not only spared from histopathological hallmarks of SIV infection but is generally histologically inconspicuous. Immune activation in SIV-infected macaques is evident, however, in the postacute phase of the infection by RNA-profiling (Roberts et al, 2004) and on isolated microglia of SIV-infected macaques Pharmacological action of memantine F Meisner et al (Scheller et al, 2005). Consequently, the neurochemical dysfunction observed may be likely due to indirect toxicity mediated by a transient immune activation after the peak viremia and the subsequent release of detrimental factors or could be due to the direct toxic potential of the viral proteins in that time frame.…”

Section: Discussionmentioning

confidence: 99%

Memantine Upregulates BDNF and Prevents Dopamine Deficits in SIV-Infected Macaques: A Novel Pharmacological Action of Memantine

Meisner

Scheller

Kneitz

et al. 2007

Neuropsychopharmacol

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N-methyl-D-aspartate (NMDA) receptor activation is involved in the pathogenetic cascades of neurodegenerative disorders including human immunodeficiency virus (HIV) dementia. Memantine, an uncompetitive NMDA receptor antagonist, which has been recently approved for the treatment of Alzheimer's disease, is being discussed as a potential adjunctive therapeutic substance for HIV dementia. We used simian immunodeficiency virus-infected rhesus macaques to assess the effects of memantine on brain dysfunction and brain pathology within 3-5 months after initial infection during early asymptomatic stage of disease. We had shown previously that within this time frame, marked changes were evident in the dopaminergic systems. Memantine was administered two weeks post infection, at peak viremia, in order to prevent early NMDA receptor activation due to immune mediators. We found that memantine prevented onset of dopamine deficits in the brains of SIV-infected macaques, without affecting early brain pathology or peripheral course of infection. Memantine specifically upregulated mRNA and protein expression of the neurotrophic factor brain-derived neurotrophic factor (BDNF), suggesting that the protective effect of memantine on dopamine function may be mechanistically remote from NMDA receptor antagonism. This novel pharmacological action of memantine may also be relevant for other neurodegenerative disorders and supports the involvement of neurotrophic factors in adult brain neuroprotection.

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“…Changes in brain gene expression can be detected in the different stages of disease (9,12,13). In the CSF, proinflammatory proteins such as cytokines and chemokines are increased in patients with HIV dementia (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Metabolomic analysis of the cerebrospinal fluid reveals changes in phospholipase expression in the CNS of SIV-infected macaques

Wikoff¹,

Pendyala²,

Siuzdak³

et al. 2008

J. Clin. Invest.

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127

113

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HIV infiltrates the CNS soon after an individual has become infected with the virus, and can cause dementia and encephalitis in late-stage disease. Here, a global metabolomics approach was used to find and identify metabolites differentially regulated in the cerebrospinal fluid (CSF) of rhesus macaques with SIV-induced CNS disease, as we hypothesized that this might provide biomarkers of virus-induced CNS damage. The screening platform used a non-targeted, mass-based metabolomics approach beginning with capillary reverse phase chromatography and electrospray ionization with accurate mass determination, followed by novel, nonlinear data alignment and online database screening to identify metabolites. CSF was compared before and after viral infection. Significant changes in the metabolome specific to SIV-induced encephalitis were observed. Metabolites that were increased during infection-induced encephalitis included carnitine, acyl-carnitines, fatty acids, and phospholipid molecules. The elevation in free fatty acids and lysophospholipids correlated with increased expression of specific phospholipases in the brains of animals with encephalitis. One of these, a phospholipase A2 isoenzyme, is capable of releasing a number of the fatty acids identified. It was expressed in different areas of the brain in conjunction with glial activation, rather than linked to regions of SIV infection and inflammation, indicating widespread alterations in infected brains. The identification of specific metabolites as well as mechanisms of their increase illustrates the potential of mass-based metabolomics to address problems in CNS biochemistry and neurovirology, as well as neurodegenerative diseases.

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Acute SIV infection of the brain leads to upregulation of IL6 and interferon-regulated genes: expression patterns throughout disease progression and impact on neuroAIDS

Cited by 75 publications

References 62 publications

Enrichment and Persistence of Virus-Specific CTL in the Brain of Simian Immunodeficiency Virus-Infected Monkeys Is Associated with a Unique Cytokine Environment

Enrichment and Persistence of Virus-Specific CTL in the Brain of Simian Immunodeficiency Virus-Infected Monkeys Is Associated with a Unique Cytokine Environment

Memantine Upregulates BDNF and Prevents Dopamine Deficits in SIV-Infected Macaques: A Novel Pharmacological Action of Memantine

Metabolomic analysis of the cerebrospinal fluid reveals changes in phospholipase expression in the CNS of SIV-infected macaques

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