The neurokinin receptor (NK1R), the substance P-preferring receptor, is a novel therapeutic target for neuroAIDS. Neurokinin-1 receptor antagonists (NK1RA) have antiviral activity, positive immunomodulatory effects and neurobehavioral effects. We have demonstrated significant ex vivo anti-HIV activity in monocyte- derived macrophages of NK1RA, which include the FDA licensed drug, aprepitant. The antiviral effect is mediated, in part, through CCR5 down-regulation. Aprepitant crosses the blood-brain barrier. Aprepitant is safe in rhesus macaques, and we have an ongoing two-week blinded Phase IB clinical safety trial of aprepitant in HIV-infected humans (NCT00428519). In this new program-project application, we propose a novel series of studies which will determine the mechanism of action of NK1R. There are three interactive preclinical and clinical projects, which target the development of NK1RA therapy for neuroAIDS: 1) Cellular Mechanisms-Neurokinin-1 R Antagonists in the Brain and Immune System;2) Immune Mechanisms-Anti- HIV Actions of Neurokinin-1 R Antagonists in Depression;and 5) Phase IB Clinical Trial of Neurokinin-1 R Antagonist-Aprepitant with ritonavir boost and direct proof of NK1R antagonism efficacy, and two Cores: A) Administration;and C) Quantitative Pharmacology and Biostatistics. The optimization of the use of NKI RA in neuroAIDS therapy is proposed and the program-project encompasses basic, translational, and clinical HIV studies of tachykinin (substance P) and NK1RA. The investigators from the Joseph Stokes, Jr. Rl, CHOP, the UPenn Schools of Medicine (Depts. of Pediatrics, Psychiatry, &Medicine) and Westat. The Philadelphia ACTU and IMPAACT CTU's, Penn-CHOP CFAR, and Penn CTSU foster the proposed interactions. These molecular, immunologic, pharmacologic, and bench-to-bedside projects address this novel therapeutic target for neuroAIDS treatment.

Public Health Relevance

(See Instructions): An integrated pre-clinical/clinical program (IPCP) is proposed to use NK1RA as anti-HIV agents in neuroAIDS. This class of receptor antagonists crosses the blood brain barrier. This NK1RA has activity as an antiviral HIV agent that improves innate immunity (Natural Killer cells) and has positive neurobehavioral effects. NK1RA are a potential novel therapy for neuroAIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01MH090325-04
Application #
8303327
Study Section
Special Emphasis Panel (ZMH1-ERB-X (02))
Program Officer
Colosi, Deborah
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$1,123,370
Indirect Cost
$323,762
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Barrett, Jeffrey S; Bajaj, Gaurav; McGuire, Jennifer et al. (2014) Modeling and simulation approach to support dosing and study design requirements for treating HIV-related neuropsychiatric disease with the NK1-R antagonist aprepitant. Curr HIV Res 12:121-31
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
Barrett, Jeffrey S; McGuire, Jennifer; Vezina, Heather et al. (2013) PET measurement of receptor occupancy as a tool to guide dose selection in neuropharmacology: are we asking the right questions? J Clin Psychopharmacol 33:725-8
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
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
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