CNS disease is a common and serious complication of HIV infection. Despite the high incidence of neurological disease, the host and viral interactions that result in the development of HIV-associated neurological disease, particularly the roles of chemokines and chemokine receptors, are not well understood. SIV infection of macaques is an ideal model system in which to study the pathogenesis of HIV infection because it recapitulates key features of HIV infection of the human CNS, most notably the development of encephalitis with characteristic histopathological changes and psychomotor impairment. The hypothesis presented is that HIV/SIV-induced neurological disease is the result of a pro-inflammatory response in the brain that is initiated by replication of neurovirulent viral strains in the CNS. Viral gene products induce the secretion of specific chemokines by native CNS cells, most notably microglia and astrocytes, as well as by infiltrating macrophages and lymphocytes. Chemokines play a dual role in down regulating viral replication and spread (MIP-1, MIP-l, and RANTES) and in upregulating inflammation through chemotaxis; the end result is chronic activation and neurodegeneration. Animals may be protected from neurological disease when there are high levels of the virus-inhibiting chemokines MIP-1, MIP-1, and RANTES in the brain. Neurological disease may result when the balance is tipped towards the chemokines, such as MCP-1 and IP-10, that induce leukocyte chemotaxis but don't suppress HIV.
The first aim of this study is to identify the role of chemokines in SIV replication and the development of inflammation in the CNS during acute through terminal SIV infection, and to identify viral genes responsible for induction of specific chemokines in macrophages, lymphocytes, microglia, and astrocytes. Next, the role of chemokine receptor expression in modulating viral load and leukocyte entry in the CNS from acute through terminal infection will be determined. The earliest time at which there is evidence of neurodegeneration will be identified, and the severity of neurodegenerative changes will be correlated with the expression of markers of activation, expression of proinflammatory cytokines and the results of behavioral/cognitive tests. Finally behavioral/cognitive changes that correlate with establishment and replication of virus in the CNS and with neurodegenerative changes in the brain will be identified.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH061189-01
Application #
6080532
Study Section
Special Emphasis Panel (ZMH1-BRB-T (01))
Program Officer
Rausch, Dianne M
Project Start
1999-09-28
Project End
2004-05-31
Budget Start
1999-09-28
Budget End
2000-05-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Witwer, Kenneth W; Gama, Lucio; Li, Ming et al. (2009) Coordinated regulation of SIV replication and immune responses in the CNS. PLoS One 4:e8129
Clements, Janice E; Mankowski, Joseph L; Gama, Lucio et al. (2008) The accelerated simian immunodeficiency virus macaque model of human immunodeficiency virus-associated neurological disease: from mechanism to treatment. J Neurovirol 14:309-17
Gray, Rachel A; Wilcox, Kristin M; Zink, M Christine et al. (2006) Impaired performance on the object retrieval-detour test of executive function in the SIV/macaque model of AIDS. AIDS Res Hum Retroviruses 22:1031-5
Babas, Tahar; Dewitt, Jesse B; Mankowski, Joseph L et al. (2006) Progressive selection for neurovirulent genotypes in the brain of SIV-infected macaques. AIDS 20:197-205
Carruth, Lucy M; Zink, M Christine; Tarwater, Patrick M et al. (2005) SIV-specific T lymphocyte responses in PBMC and lymphoid tissues of SIV-infected pigtailed macaques during suppressive combination antiretroviral therapy. J Med Primatol 34:109-21
Weed, Michael R; Steward, David J (2005) Neuropsychopathology in the SIV/macaque model of AIDS. Front Biosci 10:710-27
Overholser, Emily D; Babas, Tahar; Zink, M Christine et al. (2005) CD4-independent entry and replication of simian immunodeficiency virus in primary rhesus macaque astrocytes are regulated by the transmembrane protein. J Virol 79:4944-51
Mankowski, J L; Queen, S E; Clements, J E et al. (2004) Cerebrospinal fluid markers that predict SIV CNS disease. J Neuroimmunol 157:66-70
Barber, Sheila A; Uhrlaub, Jennifer L; DeWitt, Jesse B et al. (2004) Dysregulation of mitogen-activated protein kinase signaling pathways in simian immunodeficiency virus encephalitis. Am J Pathol 164:355-62
Overholser, Emily D; Coleman, Gary D; Bennett, Jennifer L et al. (2003) Expression of simian immunodeficiency virus (SIV) nef in astrocytes during acute and terminal infection and requirement of nef for optimal replication of neurovirulent SIV in vitro. J Virol 77:6855-66

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