Abstract

The overall objective of this proposal is to determine the role of apoptosis in HIV-1 dementia. We and others previously demonstrated apoptosis of neurons and other cell types in brain from patients with HIV-1 dementia, indicating that apoptosis is likely to contribute to neuronal loss and cognitive dysfunction in AIDS. We have shown that infection of primary human brain cultures by particular HIV-1 isolates induces neuronal apoptosis. Our studies suggest that the HIV-1 Env is an important determinant of neurodegenerative mechanisms associated with HIV-1 infection and further suggest that certain X4 or R5X4 viruses which emerge in the late stages of disease may impact disease progression in the CNS. The mechanisms that lead to neuronal apoptosis in the brain of AIDS patients in vivo have not been identified. This proposal will address several questions that are important for understanding mechanisms which lead to apoptosis to HIV-1 in dementia.
Aim 1 will characterize HIV-1 viruses in brain, CSF, and blood that induce neuronal and determine their correlation with clinical dementia. The role of HIV-1 Envs cloned directly from brain and other tissues in mechanisms. In mechanisms that lead to neuronal apoptosis will also be investigated.
Aim 2 will investigate the role of HIV-1 gp120 interactions with CXCR4 and other chemokine receptors in mechanisms that lead to neuronal apoptosis.
Aim 3 will characterize the phenotype and function of two distinct populations of microglia which differentially express CCR5 and CCR3. We will then determine their relative susceptibility to HIV-1 infection, signaling induced by HIV-1 gp120 and chemokines, and production of soluble factors that induce neuronal apoptosis. These studies will establish in vitro assays for HIV-1 neuropathogenicity which will lead to a better understanding of mechanisms of apoptosis and CNS injury in HIV-1 dementia and help to advance the development of new therapeutic strategies. These studies may also provide insights relevant for mechanisms involved in other neurodegenerative diseases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035734-06
Application #
6539901
Study Section
Special Emphasis Panel (ZRG1-AARR-6 (02))
Program Officer
Nunn, Michael
Project Start
1996-08-01
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
6
Fiscal Year
2002
Total Cost
$340,740
Indirect Cost

  Institution

Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

Agopian, Kristin; Wei, Bangdong L; Garcia, J Victor et al. (2007) CD4 and MHC-I downregulation are conserved in primary HIV-1 Nef alleles from brain and lymphoid tissues, but Pak2 activation is highly variable. Virology 358:119-35
Agopian, Kristin; Wei, Bangdong L; Garcia, J Victor et al. (2006) A hydrophobic binding surface on the human immunodeficiency virus type 1 Nef core is critical for association with p21-activated kinase 2. J Virol 80:3050-61
Ancuta, Petronela; Wang, Jianbin; Gabuzda, Dana (2006) CD16+ monocytes produce IL-6, CCL2, and matrix metalloproteinase-9 upon interaction with CX3CL1-expressing endothelial cells. J Leukoc Biol 80:1156-64
Wang, Jianbin; Gabuzda, Dana (2006) Reconstitution of human immunodeficiency virus-induced neurodegeneration using isolated populations of human neurons, astrocytes, and microglia and neuroprotection mediated by insulin-like growth factors. J Neurovirol 12:472-91
Dunfee, Rebecca; Thomas, Elaine R; Gorry, Paul R et al. (2006) Mechanisms of HIV-1 neurotropism. Curr HIV Res 4:267-78
Gorry, Paul R; Churchill, Melissa; Crowe, Suzanne M et al. (2005) Pathogenesis of macrophage tropic HIV-1. Curr HIV Res 3:53-60
Holm, Geoffrey H; Gabuzda, Dana (2005) Distinct mechanisms of CD4+ and CD8+ T-cell activation and bystander apoptosis induced by human immunodeficiency virus type 1 virions. J Virol 79:6299-311
Wang, Jianbin; Babcock, Gregory J; Choe, Hyeryun et al. (2004) N-linked glycosylation in the CXCR4 N-terminus inhibits binding to HIV-1 envelope glycoproteins. Virology 324:140-50
Holm, Geoffrey H; Zhang, Chengsheng; Gorry, Paul R et al. (2004) Apoptosis of bystander T cells induced by human immunodeficiency virus type 1 with increased envelope/receptor affinity and coreceptor binding site exposure. J Virol 78:4541-51
Bobardt, Michael D; Salmon, Patrick; Wang, Lianchun et al. (2004) Contribution of proteoglycans to human immunodeficiency virus type 1 brain invasion. J Virol 78:6567-84

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