TY - JOUR
T1 - Combination fluconazole/paroxetine treatment is neuroprotective despite ongoing neuroinflammation and viral replication in an SIV model of HIV neurological disease
AU - Meulendyke, Kelly A.
AU - Queen, Suzanne E.
AU - Engle, Elizabeth L.
AU - Shirk, Erin N.
AU - Liu, Jiayang
AU - Steiner, Joseph P.
AU - Nath, Avindra
AU - Tarwater, Patrick M.
AU - Graham, David R.
AU - Mankowski, Joseph L.
AU - Zink, M. Christine
N1 - Publisher Copyright:
© 2014, Journal of NeuroVirology, Inc.
PY - 2014/12/12
Y1 - 2014/12/12
N2 - 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.
AB - 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.
KW - CNS
KW - Fluconazole
KW - HIV
KW - Paroxetine
KW - SIV
KW - Selective serotonin reuptake inhibitor
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UR - http://www.scopus.com/inward/citedby.url?scp=84916606478&partnerID=8YFLogxK
U2 - 10.1007/s13365-014-0283-1
DO - 10.1007/s13365-014-0283-1
M3 - Article
C2 - 25227932
AN - SCOPUS:84916606478
SN - 1355-0284
VL - 20
SP - 591
EP - 602
JO - Journal of NeuroVirology
JF - Journal of NeuroVirology
IS - 6
ER -