CHEMOKINES AND CHEMOKINE RECEPTORS IN SIV ENCEPHALITIS

Summary

Principal Investigator: M CHRISTINE contact ZINK
Affiliation: Johns Hopkins University
Country: USA
Abstract: DESCRIPTION (Adapted from applicant's abstract): 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.
Funding Period: 1999-09-28 - 2004-11-30
more information: NIH RePORT

Top Publications

  1. ncbi Neuropsychopathology in the SIV/macaque model of AIDS
    Michael R Weed
    Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA
    Front Biosci 10:710-27. 2005
  2. ncbi CD4-independent entry and replication of simian immunodeficiency virus in primary rhesus macaque astrocytes are regulated by the transmembrane protein
    Emily D Overholser
    The Reterovirus Laboratory, Department of Comparitive Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 819 BRB, Baltimore, MD 21205, USA
    J Virol 79:4944-51. 2005
  3. ncbi SIV-specific T lymphocyte responses in PBMC and lymphoid tissues of SIV-infected pigtailed macaques during suppressive combination antiretroviral therapy
    Lucy M Carruth
    Department of Comparative Medicine, Johns Hopkins University School of Medicine, Jefferson Street Building, 600 N Wolfe Street, Baltimore, MD 21287, USA
    J Med Primatol 34:109-21. 2005
  4. ncbi Progressive selection for neurovirulent genotypes in the brain of SIV-infected macaques
    Tahar Babas
    Department of Comparative Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
    AIDS 20:197-205. 2006
  5. ncbi Impaired performance on the object retrieval-detour test of executive function in the SIV/macaque model of AIDS
    Rachel A Gray
    Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA
    AIDS Res Hum Retroviruses 22:1031-5. 2006
  6. ncbi The accelerated simian immunodeficiency virus macaque model of human immunodeficiency virus-associated neurological disease: from mechanism to treatment
    Janice E Clements
    Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    J Neurovirol 14:309-17. 2008
  7. ncbi Coordinated regulation of SIV replication and immune responses in the CNS
    Kenneth W Witwer
    Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
    PLoS ONE 4:e8129. 2009

Scientific Experts

  • Lucy M Carruth
  • M R Weed
  • Janice E Clements
  • M Christine Zink
  • Joseph L Mankowski
  • Tahar Babas
  • Kenneth W Witwer
  • Lucio Gama
  • Patrick M Tarwater
  • Rachel A Gray
  • Emily D Overholser
  • Angela K Brice
  • John J Varrone
  • Suzanne E Queen
  • Ming Li
  • Christopher M Bartizal
  • David R Graham
  • Kristin M Wilcox
  • Jesse B DeWitt
  • Sheila A Barber

Detail Information

Publications7

  1. ncbi Neuropsychopathology in the SIV/macaque model of AIDS
    Michael R Weed
    Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA
    Front Biosci 10:710-27. 2005
    ....
  2. ncbi CD4-independent entry and replication of simian immunodeficiency virus in primary rhesus macaque astrocytes are regulated by the transmembrane protein
    Emily D Overholser
    The Reterovirus Laboratory, Department of Comparitive Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, 819 BRB, Baltimore, MD 21205, USA
    J Virol 79:4944-51. 2005
    ....
  3. ncbi SIV-specific T lymphocyte responses in PBMC and lymphoid tissues of SIV-infected pigtailed macaques during suppressive combination antiretroviral therapy
    Lucy M Carruth
    Department of Comparative Medicine, Johns Hopkins University School of Medicine, Jefferson Street Building, 600 N Wolfe Street, Baltimore, MD 21287, USA
    J Med Primatol 34:109-21. 2005
    ..Conversely, in the setting of low initial viremia and robust T lymphocyte responses, treatment does not have a detrimental effect on the immune response...
  4. ncbi Progressive selection for neurovirulent genotypes in the brain of SIV-infected macaques
    Tahar Babas
    Department of Comparative Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
    AIDS 20:197-205. 2006
    ..CONCLUSION: These data demonstrate that the almost exclusive replication of neurovirulent genotypes in the brain seen at late-stage infection is a progressive process that begins early in infection and continues to late stage disease...
  5. ncbi Impaired performance on the object retrieval-detour test of executive function in the SIV/macaque model of AIDS
    Rachel A Gray
    Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA
    AIDS Res Hum Retroviruses 22:1031-5. 2006
    ..Given the sensitivity of ORD performance to dopaminergic dysfunction, these results further implicate dopaminergic dysfunction as a mechanism of cognitive and motor impairments in NeuroAIDS...
  6. ncbi The accelerated simian immunodeficiency virus macaque model of human immunodeficiency virus-associated neurological disease: from mechanism to treatment
    Janice E Clements
    Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    J Neurovirol 14:309-17. 2008
    ....
  7. ncbi Coordinated regulation of SIV replication and immune responses in the CNS
    Kenneth W Witwer
    Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
    PLoS ONE 4:e8129. 2009
    ..These studies further suggest that interventions should target HIV-infected individuals with increased CCL2 levels or HIV RNA in the CNS...