. We have developed the first SIV/macaque model of HAART therapy in HIV-infected individuals. These animal studies will answer questions about HIV infection and pathogenesis that cannot be answered by studying HIV infection in humans. Animal experiments are central to study tissue reservoirs and to examine the relationship between peripheral immune responses and SIV-associated neurological disease. Blood, CSF and/or tissues from infected macaques are used by each Project in the Program. The animal studies are designed to address the following questions: To what level does SIV still replicate and how much proviral DNA is present in peripheral and neurological tissues during apparently effective HAART therapy? Is it possible to further reduce the level of virus replication to be undetectable even by the most sensitive assays? Does earlier initiation of HAART therapy reduce the number of cells trafficking to the CNS and the levels of virus in tissue reservoirs? Does earlier initiation of HAART better preserve peripheral immune system function, preventing the effects of persistent immune activation that results in loss of control over virus and eventually resulting in inflammation and degeneration in the nervous system? Macaques will be inoculated with SIV using our well-characterized accelerated, consistent SIV/macaque model in which over 90% of inoculated macaques develop encephalitis by 3 months p.i. Macaques will be treated with Tenofovir (RT inhibitor), Atazanavir (protease inhibitor). Saquinavir (protease inhibitor), and Merck 206DA (integrase inhibitor) beginning at 4, 12 or 28 days after virus inoculation. Some animals will be subsequently treated with a test compound designed to purge tissue reservoirs. Other groups of animals will be used as controls for the above studies. Blood and CSF will be sampled every week for the first 6 weeks after virus inoculation and every two weeks thereafter until euthanasia. Additional macaques will be used for pharmacokinetic studies to determine the appropriate dose and frequency to achieve effective levels of a test compound that will be used to purge viral in plasma and to determine the extent to which the drug crosses the blood-brain barrier. These macaques will not be euthanized and will be used in later experiments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program Projects (P01)
Project #
5P01MH070306-09
Application #
8453383
Study Section
Special Emphasis Panel (ZMH1-ERB-F)
Project Start
Project End
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
9
Fiscal Year
2013
Total Cost
$219,873
Indirect Cost
$72,775
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Meulendyke, Kelly A; Croteau, Joshua D; Zink, M Christine (2014) HIV life cycle, innate immunity and autophagy in the central nervous system. Curr Opin HIV AIDS 9:565-71
Meulendyke, Kelly A; Ubaida-Mohien, Ceereena; Drewes, Julia L et al. (2014) Elevated brain monoamine oxidase activity in SIV- and HIV-associated neurological disease. J Infect Dis 210:904-12
Abreu, Celina M; Price, Sarah L; Shirk, Erin N et al. (2014) Dual role of novel ingenol derivatives from Euphorbia tirucalli in HIV replication: inhibition of de novo infection and activation of viral LTR. PLoS One 9:e97257
Mangus, Lisa M; Dorsey, Jamie L; Laast, Victoria A et al. (2014) Unraveling the pathogenesis of HIV peripheral neuropathy: insights from a simian immunodeficiency virus macaque model. ILAR J 54:296-303
Meulendyke, Kelly A; Queen, Suzanne E; Engle, Elizabeth L et al. (2014) Combination fluconazole/paroxetine treatment is neuroprotective despite ongoing neuroinflammation and viral replication in an SIV model of HIV neurological disease. J Neurovirol 20:591-602
Akay, Cagla; Cooper, Michael; Odeleye, Akinleye et al. (2014) Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system. J Neurovirol 20:39-53
Dorsey, Jamie L; Mangus, Lisa M; Oakley, Jonathan D et al. (2014) Loss of corneal sensory nerve fibers in SIV-infected macaques: an alternate approach to investigate HIV-induced PNS damage. Am J Pathol 184:1652-9
Witwer, Kenneth W; McAlexander, Melissa A; Queen, Suzanne E et al. (2013) Real-time quantitative PCR and droplet digital PCR for plant miRNAs in mammalian blood provide little evidence for general uptake of dietary miRNAs: limited evidence for general uptake of dietary plant xenomiRs. RNA Biol 10:1080-6
Russell, Julia N; Clements, Janice E; Gama, Lucio (2013) Quantitation of gene expression in formaldehyde-fixed and fluorescence-activated sorted cells. PLoS One 8:e73849
Metcalf Pate, Kelly A; Lyons, Claire E; Dorsey, Jamie L et al. (2013) Platelet activation and platelet-monocyte aggregate formation contribute to decreased platelet count during acute simian immunodeficiency virus infection in pig-tailed macaques. J Infect Dis 208:874-83

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