. 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 #
5P01MH070306-10
Application #
8582576
Study Section
Special Emphasis Panel (ZMH1-ERB-F)
Project Start
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
10
Fiscal Year
2014
Total Cost
$205,908
Indirect Cost
$68,028
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Beck, Sarah E; Queen, Suzanne E; Metcalf Pate, Kelly A et al. (2018) An SIV/macaque model targeted to study HIV-associated neurocognitive disorders. J Neurovirol 24:204-212
Croteau, Joshua D; Engle, Elizabeth L; Queen, Suzanne E et al. (2017) Marked Enteropathy in an Accelerated Macaque Model of AIDS. Am J Pathol 187:589-604
Gannon, Patrick J; Akay-Espinoza, Cagla; Yee, Alan C et al. (2017) HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via ?-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation. Am J Pathol 187:91-109
Gama, Lucio; Abreu, Celina M; Shirk, Erin N et al. (2017) Reactivation of simian immunodeficiency virus reservoirs in the brain of virally suppressed macaques. AIDS 31:5-14
Williams, Dionna W; Engle, Elizabeth L; Shirk, Erin N et al. (2016) Splenic Damage during SIV Infection: Role of T-Cell Depletion and Macrophage Polarization and Infection. Am J Pathol 186:2068-2087
Saylor, Deanna; Dickens, Alex M; Sacktor, Ned et al. (2016) HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment. Nat Rev Neurol 12:234-48
Mangus, Lisa M; Dorsey, Jamie L; Weinberg, Rachel L et al. (2016) Tracking Epidermal Nerve Fiber Changes in Asian Macaques: Tools and Techniques for Quantitative Assessment. Toxicol Pathol 44:904-12
Avalos, Claudia R; Price, Sarah L; Forsyth, Ellen R et al. (2016) Quantitation of Productively Infected Monocytes and Macrophages of Simian Immunodeficiency Virus-Infected Macaques. J Virol 90:5643-5656
Beck, Sarah E; Queen, Suzanne E; Viscidi, Raphael et al. (2016) Central nervous system-specific consequences of simian immunodeficiency virus Gag escape from major histocompatibility complex class I-mediated control. J Neurovirol 22:498-507
Drewes, Julia L; Meulendyke, Kelly A; Liao, Zhaohao et al. (2015) Quinolinic acid/tryptophan ratios predict neurological disease in SIV-infected macaques and remain elevated in the brain under cART. J Neurovirol 21:449-63

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