YEARS

1999-2005

AUTHORS

Howard S. Fox

TITLE

PERIPHERAL VIRAL LOAD AND SIV-INDUCED CNS DYSFUNCTION

ABSTRACT

Description (adapted from applicant's abstract): This is a revised five-year R01 grant application. A research team headed by Dr. Howard Fox with collaborators Steven Henriksen (electrophysiologist) and John Polich (bio-statistician) and research support staff from the Scripps Research Institute, La Jolla, CA has proposed to examine the relationship between virus levels and associated CNS disease in SIV-infected macaques. This group proposes to use an SIV-rhesus macaque model to test their hypothesis that CNS virus-associated pathology can be blocked, limited or reversed by the administration of antiviral drugs. Both mono-therapy (PMPA) and combination-therapy (PMPA and ZDV) will be used at various stages of infection. Further, the proposed research seeks to describe and determine the cause of CNS tissue damage associated with CNS dysfunction. CNS dysfunction will be detected by physiological monitoring during SIV infection. Their three Specific Aims will determine: 1.) Whether early antiviral treatment (two weeks PI) prevents or reduces the CNS pathology and whether termination of the treatment will result in the development of CNS symptoms and pathology, 2.) The histopathological characteristics of CNS pathology in treated and untreated SIV-infected macaques during a serial sacrifice experiment and 3.) Whether CNS abnormalities are reversible by lowering viral load in chronically infected macaques by initiating antiviral therapy at five months PI. A total of 44 Rhesus macaques will be used in the proposed experiments. All animals will be monitored by a well thought out series of assays and physiological assessments followed by detailed tissue analysis at necropsy.

FUNDED PUBLICATIONS

  • Induction of pathogenic sets of genes in macrophages and neurons in NeuroAIDS.
  • Regulation of indoleamine 2,3-dioxygenase expression in simian immunodeficiency virus-infected monkey brains.
  • Patterns of gene dysregulation in the frontal cortex of patients with HIV encephalitis.
  • Impaired performance on a rhesus monkey neuropsychological testing battery following simian immunodeficiency virus infection.
  • Antiviral treatment normalizes neurophysiological but not movement abnormalities in simian immunodeficiency virus-infected monkeys.
  • Distinct clonal repertoire of brain CD8+ cells in simian immunodeficiency virus infection.
  • Development and characterization of positively selected brain-adapted SIV.
  • CD163 identifies a unique population of ramified microglia in HIV encephalitis (HIVE).
  • Acute SIV infection of the brain leads to upregulation of IL6 and interferon-regulated genes: expression patterns throughout disease progression and impact on neuroAIDS.
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    27 TRIPLES      17 PREDICATES      28 URIs      9 LITERALS

    Subject Predicate Object
    1 grants:9e4b95746af0f0687ff6bbed74b6aead sg:abstract Description (adapted from applicant's abstract): This is a revised five-year R01 grant application. A research team headed by Dr. Howard Fox with collaborators Steven Henriksen (electrophysiologist) and John Polich (bio-statistician) and research support staff from the Scripps Research Institute, La Jolla, CA has proposed to examine the relationship between virus levels and associated CNS disease in SIV-infected macaques. This group proposes to use an SIV-rhesus macaque model to test their hypothesis that CNS virus-associated pathology can be blocked, limited or reversed by the administration of antiviral drugs. Both mono-therapy (PMPA) and combination-therapy (PMPA and ZDV) will be used at various stages of infection. Further, the proposed research seeks to describe and determine the cause of CNS tissue damage associated with CNS dysfunction. CNS dysfunction will be detected by physiological monitoring during SIV infection. Their three Specific Aims will determine: 1.) Whether early antiviral treatment (two weeks PI) prevents or reduces the CNS pathology and whether termination of the treatment will result in the development of CNS symptoms and pathology, 2.) The histopathological characteristics of CNS pathology in treated and untreated SIV-infected macaques during a serial sacrifice experiment and 3.) Whether CNS abnormalities are reversible by lowering viral load in chronically infected macaques by initiating antiviral therapy at five months PI. A total of 44 Rhesus macaques will be used in the proposed experiments. All animals will be monitored by a well thought out series of assays and physiological assessments followed by detailed tissue analysis at necropsy.
    2 sg:endYear 2005
    3 sg:fundingAmount 2050237.0
    4 sg:fundingCurrency USD
    5 sg:hasContribution contributions:6779097f1ac685ce855d7749023862ce
    6 sg:hasFieldOfResearchCode anzsrc-for:11
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    9 sg:hasFundedPublication articles:135df2717e514673f70109333ac5fa20
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    18 sg:hasFundingOrganization grid-institutes:grid.416868.5
    19 sg:hasRecipientOrganization grid-institutes:grid.214007.0
    20 sg:language English
    21 sg:license http://scigraph.springernature.com/explorer/license/
    22 sg:scigraphId 9e4b95746af0f0687ff6bbed74b6aead
    23 sg:startYear 1999
    24 sg:title PERIPHERAL VIRAL LOAD AND SIV-INDUCED CNS DYSFUNCTION
    25 sg:webpage http://projectreporter.nih.gov/project_info_description.cfm?aid=6639099
    26 rdf:type sg:Grant
    27 rdfs:label Grant: PERIPHERAL VIRAL LOAD AND SIV-INDUCED CNS DYSFUNCTION
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