This is a revised Stage II CEBRA application, a competing renewal and extension of our Stage I program to develop a new model for HIV-1 infection in the CNS employing immunocompetent, conventional mice. In Stage I we demonstrated for the first time that there HIV-1 can replicate in several types of primary murine cells and we constructed EcoHIV, a chimeric HIV-1 capable of entry, replication, and spread in mouse lymphocytes. Importantly, since the first submission, we found that mice inoculated i.v. with EcoHIV become persistently infected at high frequency as indicated by seroconversion and presence of virus in the spleen and peritoneal macrophages over a 3 month period. Some animals showed evidence of virus infiltration into the brain, elevated expression of genes associated with inflammation in brain tissue, and brain lesions one of which contained structures that resembled multinucleated giant cells seen other retroviral neuropathies. We believe that these results bring us closer to the proof-of-principle of the proposed model. We have revised the application in light of these findings and the Reviewers' suggestions with an overall goal of investigating HIV-1 infection and pathogenesis of the nervous system in mice. We plan to identify the similarities between HIV-1 neuropathogenesis in this model and human disease and to employ them to investigate in detail the roles of HIV-1 replication dynamics and viral envelope in initiation and progression of brain disease. Initial studies on the effect of morphine in this model are also proposed.
The Specific Aims are: 1) To characterize systemic EcoHIV infection and virus entry into the brain in immunocompetent inbred mice; 2) To establish an experimental paradigm of HAD-like neuropathogenesis in the EcoHIV mouse model; 3) To investigate contribution of specific HIV-1 gp120 domains to neuropathogenesis in the EcoHIV mouse model; 4) To investigate HIV-1 mediated neuropathogenesis in the mouse as a function of EcoHIV-1 virulence; 5) (Exploratory Aim): To explore modulation of HIV-1 replication in mice by morphine. We shall investigate EcoHIV replication in vitro and in vivo using DNA- and RNA PCR, Elisa, and immunohistochemistry coupled with laser capture microdissection. Pathological changes will be scored by microscopy of tissue sections, by flow cytometry, and by evaluation of changes in protein and gene expression in the brain by IHC, Elisa, RNA- and real time-PCR, and protein arrays. This Program will develop and test chimeric HIV-1 species competent to replicate and induce disease in any conventional mouse and meets the CEBRA criteria as high impact/high risk research. This model will be valuable for studies of HIV-1 neuropathogenesis, impact of addiction and drugs of abuse, as well as development of therapies and vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA017618-01A1
Application #
6847672
Study Section
Special Emphasis Panel (ZRG1-AARR-D (04))
Program Officer
Pollock, Jonathan D
Project Start
2004-07-15
Project End
2009-04-30
Budget Start
2004-07-15
Budget End
2005-04-30
Support Year
1
Fiscal Year
2004
Total Cost
$492,805
Indirect Cost
Name
St. Luke's-Roosevelt Institute for Health Sciences
Department
Type
DUNS #
623216371
City
New York
State
NY
Country
United States
Zip Code
10019
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
Nitkiewicz, Jadwiga; Borjabad, Alejandra; Morgello, Susan et al. (2017) HIV induces expression of complement component C3 in astrocytes by NF-?B-dependent activation of interleukin-6 synthesis. J Neuroinflammation 14:23
Geraghty, Patrick; Hadas, Eran; Kim, Boe-Hyun et al. (2017) HIV infection model of chronic obstructive pulmonary disease in mice. Am J Physiol Lung Cell Mol Physiol 312:L500-L509
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Moidunny, Shamsudheen; Matos, Marco; Wesseling, Evelyn et al. (2016) Oncostatin M promotes excitotoxicity by inhibiting glutamate uptake in astrocytes: implications in HIV-associated neurotoxicity. J Neuroinflammation 13:144
Rappaport, Jay; Volsky, David J (2015) Role of the macrophage in HIV-associated neurocognitive disorders and other comorbidities in patients on effective antiretroviral treatment. J Neurovirol 21:235-41
Sindberg, Gregory M; Sharma, Umakant; Banerjee, Santanu et al. (2015) An infectious murine model for studying the systemic effects of opioids on early HIV pathogenesis in the gut. J Neuroimmune Pharmacol 10:74-87
He, Hongxia; Sharer, Leroy R; Chao, Wei et al. (2014) Enhanced human immunodeficiency virus Type 1 expression and neuropathogenesis in knockout mice lacking Type I interferon responses. J Neuropathol Exp Neurol 73:59-71
Saini, Manisha; Potash, Mary Jane (2014) Chronic, highly productive HIV infection in monocytes during supportive culture. Curr HIV Res 12:317-24
Potash, Mary Jane; Hadas, Eran; Volsky, David J (2014) Response to 'Remarks on the article of Hadas et al.: Transmission of chimeric HIV by mating in conventional mice: prevention by pre-exposure antiretroviral therapy and reduced susceptibility during estrus'. Dis Model Mech 7:178-9

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