Peripheral neuropathy is the most common neurological complication of HIV-1 infection, affecting over onethird of infected individuals including those treated with antiretroviral therapy. The paradoxical increased incidence of peripheral neuropathy seen in HIV-infected patients following widespread use of HAART regimens reflects the additive effects of HIV-induced PNS damage and anti-retroviral neurotoxicity. Our extensive studies in SIV-infected macaques have detailed PNS damage closely resembling HIV-induced PNS disease;these findings set the stage for also examining neurotoxic damage caused by HAART regimens in the SIV/macaque model. Our follow-up studies have shown significant epidermal nerve fiber loss in SIV-infected macaques on HAART. Thus, despite suppression of viral replication, peripheral nerve damage still develops in SIV-infected macaques treated with HAART. This finding establishes a valuable SIV/macaque model for studying the mechanisms underlying peripheral nervous system damage caused by HIV and antiretroviral therapy. In studies focused on groups of animals including A) uninfected controls, B) SIV-infected, 3) SIV-infected HAART-treated, and 4) uninfected animals receiving HAART, we have three aims: 1) To determine whether HAART treatment that effectively controls SIV replication nonetheless exacerbates SIV-induced slowing of nerve conduction in small sensory nerve fibers (C-fibers), 2) To determine whether administration of HAART in SIV infection and independent of viral infection induces mitochondrial dysfunction in the PNS and 3) To determine whether administration of HAART impairs nerve regeneration in SIV infection (and independently of infection) using our macaque intracutaneous axotomy model of nerve regeneration. These proposed studies in the SIV/macaque HAART model will enable us to dentify the specific contributions to PNS damage attributable to virus versus neurotoxic HAART regimens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program Projects (P01)
Project #
5P01MH070306-10
Application #
8582584
Study Section
Special Emphasis Panel (ZMH1-ERB-F)
Project Start
Project End
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
10
Fiscal Year
2014
Total Cost
$202,992
Indirect Cost
$68,025
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

Showing the most recent 10 out of 58 publications