The number of HIV (human immunodeficiency virus)-positive individuals has risen over recent years mainly because combination antiretroviral therapy (cART) is helping these patients live longer. However, the prevalence of HIV-Associated Neurocognitive Disorders (HAND) has also risen since cART drugs in general do not effectively cross the blood-brain-barrier. To address this issue, we propose to evaluate a new type of treatment targeted for HAND. In patients with HAND and in animal models of the disease process, we and others have accumulated evidence that neurons are damaged. Additionally, emerging evidence from our laboratory and others suggests that adult neuroprogenitor cells (aNPCs) are also decreased in the brains of patients with NeuroAIDs. Active neurogenesis normally occurs throughout life in the dentate gyrus in the hippocampus. Newly generated neurons are incorporated into the neural network, contributing to certain types of learning and memory. Intriguingly, hippocampal neurogenesis is significantly altered in several neurodegenerative diseases in addition to HAND. Recently, we reported that the HIV-envelope glycoprotein gp120, which is associated with HAND pathogenesis, inhibits proliferation of adult neural progenitor cells in vitro and in vivo in the dentate gyrus of the hippocampus in a NeuroAIDS rodent model, the HIV/gp120- transgenic mouse. As potential treatment, we and our collaborators have synthesized new peptide inhibitors of chemokine receptors (CXCR4 and CCR5, which are co-receptors for HIV/gp120), and found that these novel synthetically and modularly modified (SMM)-chemokines block the inhibitory effect of gp120 on neural progenitor proliferation in vitro. Here, we propose to investigate the effectiveness of SMM-chemokines in vivo, beginning with new, very selective and non-toxic CXCR4 antagonists. In particular, we propose to investigate whether transnasal (also called intranasal) application of SMM-chemokines can prevent the decrease in proliferation of adult neural progenitors in mouse models of NeuroAIDS. Notably, we have recently shown that transnasally administered-peptides are preferentially delivered to the brain, and other peptides have been approved in humans by the FDA for brain delivery in this fashion. We list the following Specific Aim: (1) To investigate whether transnasal application of SMM-chemokine analogs protects adult neurons and restores the proliferation of adult hippocampal progenitors in HIV/gp120-transgenic mice. Note that in future work, we plan to test for 'generalization'of the effect of the SMM-chemokine analogs by investigating whether transnasal application of SMM-chemokine analogs also protects neurons and restores the proliferation of adult hippocampal progenitors in a second NeuroAIDS model, consisting of NOD/scid-IL- 2Rgcnull mice that are reconstituted with human hematopoietic CD34+ stem cells and then infected with HIV-1. This model, as developed by our collaborator Dr. Howard Gendelman and colleagues, while more difficult to utilize, closely mimics human HAND progression and cognitive dysfunction.

Public Health Relevance

Cognitive dysfunction in AIDS (HIV-Associated Neurocognitive Disorders or HAND)) remains a substantial clinical problem;recent studies have shown that not only are neurons damaged in this disorder but also the ability to make new neurons (adult neurogenesis) is decreased in the brains of human patients with HAND. The preservation of old neurons and the neurogenesis of new neurons from adult precursor/stem cells are both thought to be important for learning and memory. Thus, the preservation of neurons and the restoration of adult neurogenesis, as planned here with novel, selective and non-toxic peptide chemokine analogs, is relevant to the therapy of HAND.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS083415-02
Application #
8739326
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2013-09-30
Project End
2015-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Nakanishi, Nobuki; Kang, Yeon-Joo; Tu, Shichun et al. (2016) Differential Effects of Pharmacologic and Genetic Modulation of NMDA Receptor Activity on HIV/gp120-Induced Neuronal Damage in an In Vivo Mouse Model. J Mol Neurosci 58:59-65
Henry, Brook L; Geyer, Mark A; Buell, Mahalah R et al. (2014) Prepulse inhibition in HIV-1 gp120 transgenic mice after withdrawal from chronic methamphetamine. Behav Pharmacol 25:12-22
Fazeli, Pariya L; Doyle, Katie L; Scott, J Cobb et al. (2014) Shallow encoding and forgetting are associated with dependence in instrumental activities of daily living among older adults living with HIV infection. Arch Clin Neuropsychol 29:278-88
Iudicello, Jennifer E; Morgan, Erin E; Gongvatana, Assawin et al. (2014) Detrimental impact of remote methamphetamine dependence on neurocognitive and everyday functioning in older but not younger HIV+ adults: evidence for a legacy effect? J Neurovirol 20:85-98
Marquine, MarĂ­a J; Iudicello, Jennifer E; Morgan, Erin E et al. (2014) ""Frontal systems"" behaviors in comorbid human immunodeficiency virus infection and methamphetamine dependency. Psychiatry Res 215:208-16
Moore, Raeanne C; Fazeli, Pariya L; Jeste, Dilip V et al. (2014) Successful cognitive aging and health-related quality of life in younger and older adults infected with HIV. AIDS Behav 18:1186-97
Dufour, Catherine A; Marquine, Maria J; Fazeli, Pariya L et al. (2013) Physical exercise is associated with less neurocognitive impairment among HIV-infected adults. J Neurovirol 19:410-7
Weber, Erica; Morgan, Erin E; Iudicello, Jennifer E et al. (2013) Substance use is a risk factor for neurocognitive deficits and neuropsychiatric distress in acute and early HIV infection. J Neurovirol 19:65-74
Doyle, Katie L; Morgan, Erin E; Morris, Sheldon et al. (2013) Real-world impact of neurocognitive deficits in acute and early HIV infection. J Neurovirol 19:565-73
Minassian, Arpi; Henry, Brook L; Woods, Steven Paul et al. (2013) Prepulse inhibition in HIV-associated neurocognitive disorders. J Int Neuropsychol Soc 19:709-17

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