HIV CNS disease is consistently associated with infiltration and activation of macrophages/microglia, enhanced production of proinflammatory cytokines, increased expression of proapoptotic and neurotoxic mediators, and neuronal loss. A number of neuroprotective therapeutics are being examined, but no single agent has emerged as the solution to the inflammatory and neurodegenerative effects of HIV in the CNS. The recent identification of the tetracycline derivative, minocycline, as a potent anti-inflammatory and neuroprotective drug that also inhibits HIV replication in macrophages, microglial cells, and astrocytes demands the examination of this readily available generic drug as a neuroprotective agent in HIV infection. We have developed an accelerated, consistent SIV/macaque model (SIV-AC) of HIV CNS disease in which over 90% of infected animals develop encephalitis with neurodegeneration as evidenced by increased expression of B-APP and B-amyloid and evidence of neuronal degeneration/apoptosis in the CSF and brain. This model recapitulates the acute, asymptomatic, and terminal characteristics of HIV infection in humans on a highly reproducible time schedule. Our recent studies using this model have demonstrated that the development of SIV encephalitis coincides with an imbalance between the antiapoptotic ERK signaling pathways and the proapoptotic JNK and p38 signaling pathways, representing a failure to maintain a homeostatic balance in the CNS. Our hypothesis is that minocycline will play a dual neuroprotective role in SIV-infected macaques: a) by inhibiting pathologic activation of p38 thus reestablishing a balance between pro-and antiapoptotic pathways, and b) by inhibiting SIV replication and hence the production of viral neurotoxic proteins in the CNS. This application proposes integrated in vivo and in vitro studies to examine the mechanisms by which minocycline exerts its palliative effects on the CNS.
In Aim 1 we propose to measure the effects of minocycline on virus replication and on the development of CNS inflammatory and neurodegenerative changes in SIV-infected macaques.
In Aims 2 and 3 we will identify the mechanism(s) by which minocycline protects against neurotoxicity and suppresses SIV/HIV replication in macrophages, microglia and astrocytes. Theses mechanistic studies are important given the potential of minocycline to act not only as a neuroprotective agent but also as a viral suppressive agent in the CNS. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH069116-04
Application #
7213337
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Joseph, Jeymohan
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$575,876
Indirect Cost
Name
Johns Hopkins University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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
Meulendyke, Kelly A; Pletnikov, Mikhail V; Engle, Elizabeth L et al. (2012) Early minocycline treatment prevents a decrease in striatal dopamine in an SIV model of HIV-associated neurological disease. J Neuroimmune Pharmacol 7:454-64
Eugenin, Eliseo A; Clements, Janice E; Zink, M Christine et al. (2011) Human immunodeficiency virus infection of human astrocytes disrupts blood-brain barrier integrity by a gap junction-dependent mechanism. J Neurosci 31:9456-65
Graham, David R; Gama, Lucio; Queen, Suzanne E et al. (2011) Initiation of HAART during acute simian immunodeficiency virus infection rapidly controls virus replication in the CNS by enhancing immune activity and preserving protective immune responses. J Neurovirol 17:120-30
Clements, Janice E; Gama, Lucio; Graham, David R et al. (2011) A simian immunodeficiency virus macaque model of highly active antiretroviral treatment: viral latency in the periphery and the central nervous system. Curr Opin HIV AIDS 6:37-42
Roberts, Toni K; Eugenin, Eliseo A; Morgello, Susan et al. (2010) PrPC, the cellular isoform of the human prion protein, is a novel biomarker of HIV-associated neurocognitive impairment and mediates neuroinflammation. Am J Pathol 177:1848-60
Zink, M Christine; Brice, Angela K; Kelly, Kathleen M et al. (2010) Simian immunodeficiency virus-infected macaques treated with highly active antiretroviral therapy have reduced central nervous system viral replication and inflammation but persistence of viral DNA. J Infect Dis 202:161-70
Mankowski, Joseph L; Queen, Suzanne E; Fernandez, Caroline S et al. (2008) Natural host genetic resistance to lentiviral CNS disease: a neuroprotective MHC class I allele in SIV-infected macaques. PLoS One 3:e3603
Clements, Janice E; Mankowski, Joseph L; Gama, Lucio et al. (2008) The accelerated simian immunodeficiency virus macaque model of human immunodeficiency virus-associated neurological disease: from mechanism to treatment. J Neurovirol 14:309-17
Follstaedt, Susan C; Barber, Sheila A; Zink, M Christine (2008) Mechanisms of minocycline-induced suppression of simian immunodeficiency virus encephalitis: inhibition of apoptosis signal-regulating kinase 1. J Neurovirol 14:376-88

Showing the most recent 10 out of 15 publications