The overarching goal of this investigation is to understand the mechanism(s) whereby the tachykinin neuropeptide, substance P (SP), and its preferred receptor, Neurokinin-lR (NK1R) modulate the immunopathogenesis of HIV as central mediators in the interaction between the immune and nervous systems. Our major hypothesis is that altered SP and NK1R, are mechanistically important in HIV pathogenesis and that this receptor and its ligand are altered in association with neurocognitive changes and life stress and depression in HIV-infected individuals. We showed that the non-peptide SP antagonist (CP-96,345) inhibits HIV replication in human mononuclear phagocytes through down-regulation of CCR5, the chemokine receptor, the principal co-receptor for HIV entry into macrophages and also by NK1R antagonist inhibition of endogenous SP production. The SP autocrine loop has an important role in regulating cytokine and inflammatory responses. HIV reciprocally enhances SP expression in human immune cells, eliciting a "feed-forward cycle". We discovered that cell differentiation in vitro from monocyte to macrophage phenotype (THP cells) results in the expression of both the NK1R-T (truncated) and NK1R-F (full-length), whereas the monocyte cell expresses only NK1R-T. The qualitative and quantitative expression of NK1R and its truncated (NK1R-T) and full length forms (NK1R-F) have functional consequences for calcium flux in macrophages. In the brain cingulate cortex, mRNA expression of both the NK1R-T and NK1R-F are reduced in HIV-infected subjects. We will use cells from both the immune and the CNS systems, including peripheral monocyte-macrophages and cells obtained from select human brain regions to examine these mechanisms. We will examine the cell biology of the interaction between NK1R (NK1R-F and NK1R-T) and HIV and chemokine receptors.
Our aims are: (1) To investigate expression of NK-1RF in monocyte-derived macrophages and their associations with CCR5, CD4, Fractalkine, and IL-8. (2) We will investigate the physical and functional interactions between NK1R-T, NK1R-F receptors and CCR5. (3) We will explore the role of cytosolic Ca2+ increase in the cross-talk between NK1R-F, NK1R-T, and CCR5. (4) We hypothesize that altered levels of either or both NK1R-T or NK1R-F mRNA and protein, or receptor function, are associated with alterations with cognitive function in HIV-1/AIDS infected individuals, and these effects alter CCR5-NK1R interaction. Relevance to Public Health: These studies will further lead to understanding the pathogenesis of neurocognitive changes in HIV disease and lead to unique and novel therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH049981-18
Application #
8208137
Study Section
Special Emphasis Panel (ZRG1-AARR-D (05))
Program Officer
Colosi, Deborah
Project Start
1995-07-01
Project End
2014-07-30
Budget Start
2012-02-01
Budget End
2014-07-30
Support Year
18
Fiscal Year
2012
Total Cost
$386,781
Indirect Cost
$151,656
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Tuluc, Florin; Meshki, John; Spitsin, Sergei et al. (2014) HIV infection of macrophages is enhanced in the presence of increased expression of CD163 induced by substance P. J Leukoc Biol 96:143-50
Schwartz, Lynnae; Spitsin, Sergei V; Meshki, John et al. (2013) Substance P enhances HIV-1 infection in human fetal brain cell cultures expressing full-length neurokinin-1 receptor. J Neurovirol 19:219-27
Spitsin, Sergei; Tuluc, Florin; Meshki, John et al. (2013) Analog of somatostatin vapreotide exhibits biological effects in vitro via interaction with neurokinin-1 receptor. Neuroimmunomodulation 20:247-55
Spitsin, Sergei; Stevens, Kathleen E; Douglas, Steven D (2013) Expression of substance P, neurokinin-1 receptor and immune markers in the brains of individuals with HIV-associated neuropathology. J Neurol Sci 334:18-23
Khan, Mohammad M; Douglas, Steven D; Benton, Tami D (2012) Substance P-neurokinin-1 receptor interaction upregulates monocyte tissue factor. J Neuroimmunol 242:1-8
Monaco-Shawver, Linda; Schwartz, Lynnae; Tuluc, Florin et al. (2011) Substance P inhibits natural killer cell cytotoxicity through the neurokinin-1 receptor. J Leukoc Biol 89:113-25
Meshki, John; Douglas, Steven D; Hu, Mingyue et al. (2011) Substance P induces rapid and transient membrane blebbing in U373MG cells in a p21-activated kinase-dependent manner. PLoS One 6:e25332
Douglas, Steven D; Leeman, Susan E (2011) Neurokinin-1 receptor: functional significance in the immune system in reference to selected infections and inflammation. Ann N Y Acad Sci 1217:83-95
Meshki, John; Douglas, Steven D; Lai, Jian-Ping et al. (2009) Neurokinin 1 receptor mediates membrane blebbing in HEK293 cells through a Rho/Rho-associated coiled-coil kinase-dependent mechanism. J Biol Chem 284:9280-9
Tuluc, Florin; Lai, Jian Ping; Kilpatrick, Laurie E et al. (2009) Neurokinin 1 receptor isoforms and the control of innate immunity. Trends Immunol 30:271-6

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