Abstract
Effective combined antiretroviral therapy (cART) in HIV-infected patients has made HIV a treatable infection; however, debilitating HIV-associated neurocognitive disorders (HAND) can still affect approximately 50% of HIV-infected individuals even under cART. While cART has greatly reduced the prevalence of the most severe form of HAND, milder forms have increased in prevalence, leaving the total proportion of HIV-infected individuals suffering from HAND relatively unchanged. In this study, an in vitro drug screen identified fluconazole and paroxetine as protective compounds against HIV gp120 and Tat neurotoxicity. Using an accelerated, consistent SIV/macaque model of HIV-associated CNS disease, we tested the in vivo neuroprotective capabilities of combination fluconazole/paroxetine (FluPar) treatment. FluPar treatment protected macaques from SIV-induced neurodegeneration, as measured by neurofilament light chain in the CSF, APP accumulation in axons, and CaMKIIα in the frontal cortex, but did not significantly reduce markers of neuroinflammation or plasma or CNS viral loads. Since HIV and SIV neurodegeneration is often attributed to accompanying neuroinflammation, this study provides proof of concept that neuroprotection can be achieved even in the face of ongoing neuroinflammation and viral replication.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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AIDS Dementia Complex / drug therapy
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AIDS Dementia Complex / physiopathology
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AIDS Dementia Complex / virology
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Acquired Immunodeficiency Syndrome / drug therapy
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Acquired Immunodeficiency Syndrome / physiopathology
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Acquired Immunodeficiency Syndrome / virology
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism
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Animals
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
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Disease Models, Animal
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Fluconazole / pharmacology*
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Gene Expression / drug effects
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Humans
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Macaca nemestrina
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Neurofilament Proteins / cerebrospinal fluid
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Neurofilament Proteins / genetics
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Neurons / drug effects*
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Neurons / pathology
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Neurons / virology
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Nootropic Agents / pharmacology*
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Paroxetine / pharmacology*
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Primary Cell Culture
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Rats
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Selective Serotonin Reuptake Inhibitors / pharmacology*
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Simian Acquired Immunodeficiency Syndrome / cerebrospinal fluid
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Simian Acquired Immunodeficiency Syndrome / drug therapy*
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Simian Acquired Immunodeficiency Syndrome / physiopathology
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Simian Acquired Immunodeficiency Syndrome / virology
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Simian Immunodeficiency Virus / drug effects
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Simian Immunodeficiency Virus / physiology
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Viral Load / drug effects
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Virus Replication / drug effects
Substances
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Amyloid beta-Protein Precursor
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Neurofilament Proteins
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Nootropic Agents
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Serotonin Uptake Inhibitors
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neurofilament protein L
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Paroxetine
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Fluconazole
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Calcium-Calmodulin-Dependent Protein Kinase Type 2