During HIV/SIV infecfion there is chronic hyperactivation of the immune system, with circulating virus stimulating expression of type I IFNs. resulting in increased numbers of infected cells trafficking to the brain and the functional impairment of effector T cells by PDL-1 and PD-1 and IDO. In the brain, activation of microglia/macrophages and astrocytes by virus promotes the release of proinflammatory cytokines/chemokines and the induction of iNOS resulting in the production of neurotoxic reactive oxygen species (ROS). Viral and host inflammatory and neurodegenerative products alter the function of neurons, resulting in excitotoxicity and reduced expression of DA and serotonin. Our hypothesis is that the effects of continued peripheral immune system hyperactivation in HIV/SIVinfected individuals are only partly reversible and that early treatment with HAART provides a significant protective advantage to the periphery and the brain by preserving effector T cell function, reducing trafficking of acfivated/infected macrophages and T cells into the brain, stopping the inflammatory neurodegenerative process and preserving levels of DA and serotonin. We recently developed the first SIV/macaque model of highly active anti-retroviral therapy (HAART) in HIVinfected individuals. We use a therapeutic regimen that includes an RT inhibitor (Tenofovir), two protease inhibitors (Atazanavir and Saquinavir) and an integrase inhibitor (206DA - Merck). In this project we will use this model to first determine the effect of HAART administered during acute infecfion, just after acute infection or during eariy virus recrudescence on preservation of innate and adaptive immune responses in the periphery. We next will compare the ability of HAART administered at various stages of infecfion to stop the pro-inflammatory cytokine cycle in the brain, suppress virus replication, preserve immune function and prevent the development of CNS disease. Finally, we will determine the effect of HAART administered at various stages of infection on the depletion of the neurotransmitters DA and serotonin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program Projects (P01)
Project #
5P01MH070306-09
Application #
8453387
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
$200,508
Indirect Cost
$72,772
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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