The experiments proposed here are designed to address the relationship between the virus, the host's response to virus, and alterations in CNS functions. We will focus on testing the hypothesis that there is a CTL response in the CNS that serves to help control viral load, but at the cost of damage to the CNS. First, we will investigate the nature and extent of the early CTL response to SIV infection in the CNS. We will asses whether there is a regional specificity of SIV infection or CTL response in the brain. Examination of measures of oxidative stress, a common potential mechanism for many dementing conditions, will assess the potential for these CTL and other events occurring in the host/viral interaction to induce damage to the CNS. Additionally, control of CTL migration by chemokines produced by the infected CNS will be investigated. Second, we will assess the nature of the CTL response in the CNS over time, compare it to the CTL response occurring in the periphery, and relate these findings to the development of CNS functional abnormalities. In order to test whether the level of peripheral viral load plays a role in the maintenance of a CNS immune response, one group of animals will receive anti-viral treatment at two weeks post-viral inoculation, at the peak of peripheral viral load and CTL response. The potential for diminution of the CNS CTL response, versus a perpetuation, will be analyzed to determine the relationship of CNS CTL to peripheral viral load, and their joint relationship to CNS dysfunction and pathology. This will aid in the examination of whether the viral-immune interactions in the CNS compartment can occur independently of those in the blood and lymphoid tissue. Third, we will examine the clonality of CTL responses in the CNS during the acute and chronic infection to assess whether the CNS response is representative of the immune response in the peripheral compartment or whether evidence of local, possibly clonal or oligoclonal amplification occurs within the CNS. We will also use anti-viral therapy and its withdrawal to model the development of viral resistance or failure of effective therapy, and determine the vulnerability of the CNS to re-infection in this setting, and the role CNS CTL play in the response to the rebound viremia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH061224-02
Application #
6187685
Study Section
Special Emphasis Panel (ZMH1-BRB-T (01))
Program Officer
Joseph, Jeymohan
Project Start
1999-09-28
Project End
2004-05-31
Budget Start
2000-06-01
Budget End
2001-05-31
Support Year
2
Fiscal Year
2000
Total Cost
$283,377
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Marcondes, Maria Cecilia G; Burdo, Tricia H; Sopper, Sieghart et al. (2007) Enrichment and persistence of virus-specific CTL in the brain of simian immunodeficiency virus-infected monkeys is associated with a unique cytokine environment. J Immunol 178:5812-9
Roberts, Eleanor S; Huitron-Resendiz, Salvador; Taffe, Michael A et al. (2006) Host response and dysfunction in the CNS during chronic simian immunodeficiency virus infection. J Neurosci 26:4577-85
Madden, Lisa J; Zandonatti, Michelle A; Flynn, Claudia T et al. (2004) CD8+ cell depletion amplifies the acute retroviral syndrome. J Neurovirol 10 Suppl 1:58-66
Roberts, Eleanor S; Burudi, E M E; Flynn, Claudia et al. (2004) Acute SIV infection of the brain leads to upregulation of IL6 and interferon-regulated genes: expression patterns throughout disease progression and impact on neuroAIDS. J Neuroimmunol 157:81-92
Roberts, Eleanor S; Masliah, Eleizer; Fox, Howard S (2004) CD163 identifies a unique population of ramified microglia in HIV encephalitis (HIVE). J Neuropathol Exp Neurol 63:1255-64
Marcondes, Maria Cecilia G; Phillipson, Curtis A; Fox, Howard S (2003) Distinct clonal repertoire of brain CD8+ cells in simian immunodeficiency virus infection. AIDS 17:1605-11
Roberts, Eleanor S; Zandonatti, Michelle A; Watry, Debbie D et al. (2003) Induction of pathogenic sets of genes in macrophages and neurons in NeuroAIDS. Am J Pathol 162:2041-57
Burudi, E M E; Marcondes, M Cecilia G; Watry, Debbie D et al. (2002) Regulation of indoleamine 2,3-dioxygenase expression in simian immunodeficiency virus-infected monkey brains. J Virol 76:12233-41
Bonthius, Daniel J; Mahoney, Jolonda; Buchmeier, Michael J et al. (2002) Critical role for glial cells in the propagation and spread of lymphocytic choriomeningitis virus in the developing rat brain. J Virol 76:6618-35
Chismar, J D; Mondala, T; Fox, H S et al. (2002) Analysis of result variability from high-density oligonucleotide arrays comparing same-species and cross-species hybridizations. Biotechniques 33:516-8, 520, 522 passim

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