HIV-associated dementia is an important complication of viral infection and a cause of significant morbidity and mortality. The cardinal feature of HIV-1 induced neurological disease is productive viral replication in monocyte-derived macrophages (MP). Macaques infected with SIV/SHIV viruses have provided excellent working models for recapitulating the HIV-CNS disease. Although lentiviral-encephalitis (LV-E) is primarily associated with CCR5-utilizing viruses, our findings have shown that CXCR4 (X4)-utilizing SHIVs were also capable of causing the syndrome in rhesus macaques. In SHIV (X4)-infected animals, typical LV-E was almost always accompanied by concurrent opportunistic infections in the brain. Inevitably these secondary infections were accompanied by strong Th2immune responses as evident by presence of interleukin (IL)-4 in encephalitic brains. We have already established thatIL-4 enhanced both, viral replication and expression of macrophage chemoattractant protein (MCP)-I in MP cultures and that, addition of antisense IL-4 DNA curtailed viral replication in these cells. Our recent microarray analyses have confirmed up-regulation of IL-4, MCP-1, platelet-derived growth factor (PDGF)-B chain, a known inducer of MCP-1and interferon-inducible peptide, IP-10, in the brains of macaque with SHIV-encephalitis. Based on these findings, we hypothesize that: 1) PDGF, a factor that has never thus far been implicated in LV-E plays a vital role in promoting virus replication in MP, either through induction of MCP-1 or through an independent pathway, and 2) IP-10 over-expression in the brains of macaques with LV-E contributes to the end-stage neuronal dysfunction. In this application we will test the hypothesis in 4 specific Aims: 1) To define the role of PDGF in virus replication in macaque MP cultures. 2) To assess the role of IP-10 and its receptor, CXCR3 in neuronal dysfunction/death. 3) Optimize liposome:DNA complexes(LDC) containing antisense DNAs of IL-4, PDGF-B chain & MCP-1 for delivery in macaque MP cultures infected withSH1V89.6P. 4) Optimization of LDC containing antisense IL-4, PDGF-B & MCP-1 DNAs for in vivo gene delivery in small animals, such as mice before aiming gene therapy in infected macaques.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH068212-04
Application #
7060763
Study Section
Special Emphasis Panel (ZRG1-AARR-5 (03))
Program Officer
Kopnisky, Kathy Lynn
Project Start
2003-07-01
Project End
2008-05-28
Budget Start
2006-05-01
Budget End
2008-05-28
Support Year
4
Fiscal Year
2006
Total Cost
$251,205
Indirect Cost
Name
University of Kansas
Department
Pathology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
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