Grant Number: 5R01MH068212-04
Project Title: Mechanism and Therapy of SHIV Encephalitis in Macaques
PI Information: ASSOCIATE PROFESSOR SHILPA J. BUCH, sbuch@kumc.edu 

Abstract: DESCRIPTION (provided by applicant):
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.

Thesaurus Terms:
AIDS dementia complex, IP 10 protein, macrophage, pathologic process, platelet derived growth factor, simian immunodeficiency virus, virus replication
HIV envelope protein gp120, antisense nucleic acid, apoptosis, calcium flux, cytokine receptor, interferon gamma, interleukin 4, liposome, monocyte chemoattractant protein 1, neurotoxicology
Macaca mulatta, human fetus tissue, laboratory rat, tissue /cell culture

Institution: UNIVERSITY OF KANSAS MEDICAL CENTER
MSN 1039
KANSAS CITY, KS 66160
Fiscal Year: 2006
Department: PATHOLOGY AND LABORATORY MEDICINE
Project Start: 01-JUL-2003
Project End: 30-APR-2008
ICD: NATIONAL INSTITUTE OF MENTAL HEALTH
IRG: ZRG1

American Journal of Pathology. 2004;164:1557-1566.)

Neuronal Apoptosis Is Mediated by CXCL10 Overexpression in Simian Human Immunodeficiency Virus Encephalitis
 
Yongjun Sui*, Raghava Potula*, Navneet Dhillon*, David Pinson*, Shanping Li*, Avindra Nath , Carol Anderson , Jadwega Turchan , Dennis Kolson , Opendra Narayan* and Shilpa Buch*

From the Department of Microbiology, Immunology, and Molecular Genetics,* Marion Merrell Dow Laboratory of Viral Pathogenesis, University of Kansas Medical Center, Kansas City, Kansas; the Department of Neurology, The Johns Hopkins University, Baltimore, Maryland; and the Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania

Animals
Five rhesus macaque monkeys previously used to define cytokine/chemokine gene expression profiles in the brain were used in this study. The five animals were infected with SHIV89.6P and all developed acquired immune deficiency syndrome (AIDS)-defining illnesses. All five had also developed virus infection in the brain but only three of these animals developed SHIV-E as demonstrated by histopathology of nine different regions of the brain.21 Details of viral inoculation, disease course, processing of tissue samples, and histological analysis of the tissues have been described earlier.21 Prominent neuropathological changes were present in basal ganglia, motor cortex, and brain stem regions in the encephalitic animals.