Antiretroviral therapy in HIV infection preserves immune function but allows development of neurocognitive impairment (NCI) in about 50% of treated patients. We propose a new route to prevent or treat HIV-associated NCI. This application aims to test the hypothesis that induction of innate antiviral responses in monocytes can mitigate HIV infection in the brain at two levels: by preventing establishment of the HIV reservoir and by interruption of expression of neuropathogenic gene products leading to NCI. Monocytic cells are the primary target of HIV in the brain; they mediate HIV entry into the brain, but they can mount innate immune responses that block HIV infection. In vivo Type I interferon responses reduce neuropathogenesis in mice infected by chimeric HIV, EcoHIV; they restrict HIV transmission in human beings and in EcoHIV infected mice and can control SIV infection in macaques. We propose to use EcoHIV infection of conventional and various knockout mice and its induction of NCI, to define the basis of protective innate immune responses of macrophages to HIV in mice to prevent HIV infection in the brain or its associated brain disease.
The Specific Aims are: 1) to test ligands to Toll-like receptors (TLR) 2, 3, 7/8, and 9 singly and in combinations for prevention of EcoHIV transit to the brain; 2) to test TLR ligands for silencing of the HIV reservoir in the brain and reversal of NCI; 3) to define key antiviral determinants of host responses during prevention or therapy of HAND by TLR ligands in an animal model by analysis of coding and regulatory RNAs and proteins using gene expression platforms, multiplex technology, bioinformatics, and fluorescence microscopy in specific cell types. Methods will include intranasal administration of TLR ligands, digital droplet PCR for sensitive measurement of viral DNA, fear conditioning assays of behavior and learning, assay of antiviral proteins in macrophages and brain by multiplex assays and microscopy, and assays of both coding and microRNA expression by NanoString technology and identification of antiviral genes or miRNA common to responses to multiple TLR ligands that prevent or control EcoHIV infection of NCI. If successful, these studies will describe novel approaches and agents for further clinical development to treat NCI in HIV infected people and to preserve brain function.

Public Health Relevance

We constructed a new HIV that infects mice instead of people in order to study disease and control experimentally. Here using the reconstructed virus and mice, we shall test a new route to control the memory and learning losses associated with HIV by activating one of the body's own defense systems, with some treatment designed to work optimally in the brain. If successful, these studies will introduce a new therapy to prevent or tret learning problems associated with HIV infection that are not relieved by therapies currently in use.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS094146-05
Application #
9905562
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wong, May
Project Start
2016-04-01
Project End
2021-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Olson, Katherine E; Bade, Aditya N; Namminga, Krista L et al. (2018) Persistent EcoHIV infection induces nigral degeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated mice. J Neurovirol 24:398-410