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Combination fluconazole/paroxetine treatment is neuroprotective despite ongoing neuroinflammation and viral replication in an SIV model of HIV neurological disease

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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.

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Acknowledgments

These studies were funded by the National Institutes of Health (grants P30 MH075673, R01 MH087233, R01 MH085554, P01 MH070306, and P40 OD013117).

The authors thank Dr. Robert J. Adams for overseeing the health and care of the animals. We also thank Dr. Lucio Gama for assistance with the IDO qRT-PCR assay and Dr. Zhaohao Liao for assistance with the serotonin ELISA.

Conflict of interest

The authors have no conflicts of interest.

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Authors and Affiliations

  1. Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, 733 North Broadway Street, MRB 819, Baltimore, MD, 21205, USA

    Kelly A. Meulendyke, Suzanne E. Queen, Elizabeth L. Engle, Erin N. Shirk, David R. Graham, Joseph L. Mankowski & M. Christine Zink

  2. Department of Biostatistics and Epidemiology, Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA

    Jiayang Liu & Patrick M. Tarwater

  3. NINDS Translational Neuroscience Center, National Institutes of Health, Bethesda, MD, USA

    Joseph P. Steiner

  4. Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

    Avindra Nath

  5. Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    David R. Graham

  6. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Joseph L. Mankowski

  7. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Joseph L. Mankowski & M. Christine Zink

  8. Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    M. Christine Zink

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  1. Kelly A. Meulendyke
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  2. Suzanne E. Queen
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  11. M. Christine Zink
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Meulendyke, K.A., Queen, S.E., Engle, E.L. et al. 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 (2014). https://doi.org/10.1007/s13365-014-0283-1

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