title: Combination fluconazole/paroxetine treatment is neuroprotective despite ongoing neuroinflammation and viral replication in an SIV model of HIV neurological disease.
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.
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, 733 North Broadway Street, MRB 819, Baltimore, MD, 21205, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Meulendyke
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Queen
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Engle
authors.forename: Erin N
authors.initials: EN
authors.lastname: Shirk
authors.forename: Jiayang
authors.initials: J
authors.lastname: Liu
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Steiner
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Tarwater
authors.forename: David R
authors.initials: DR
authors.lastname: Graham
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Mankowski
authors.forename: M Christine
authors.initials: MC
authors.lastname: Zink
mesh_terms: D015526:AIDS Dementia Complex / Q000188:drug therapy / Q000503:physiopathology / Q000821:virology; D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000503:physiopathology / Q000821:virology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015725:Fluconazole / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008254:Macaca nemestrina; D016900:Neurofilament Proteins / Q000134:cerebrospinal fluid / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000821:virology; D018697:Nootropic Agents / Q000494:pharmacology*; D017374:Paroxetine / Q000494:pharmacology*; D061251:Primary Cell Culture; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000503:physiopathology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000502:physiology; D019562:Viral Load / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D016564:Amyloid beta-Protein Precursor; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D015725:Fluconazole; D016900:Neurofilament Proteins; D018697:Nootropic Agents; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors; C044882:neurofilament protein L