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Journal of NeuroVirology

, Volume 23, Issue 2, pp 290–303 | Cite as

The anticancer drug sunitinib promotes autophagyand protects from neurotoxicity in an HIV-1 Tat model of neurodegeneration

  • Jerel A. Fields
  • Jeff Metcalf
  • Cassia Overk
  • Anthony Adame
  • Brian Spencer
  • Wolfgang Wrasidlo
  • Jazmin Florio
  • Edward Rockenstein
  • Johnny J. He
  • Eliezer MasliahEmail author
Article

Abstract

Despite the success of antiretroviral therapies to control systemic HIV-1 infection, the prevalence of HIV-associated neurocognitive disorders (HANDs) has not decreased among aging patients with HIV. Autophagy pathway alterations, triggered by HIV-1 proteins including gp120, Tat, and Nef, might contribute to the neurodegenerative process in aging patients with HAND. Although no treatments are currently available to manage HAND, we have previously shown that sunitinib, an anticancer drug that blocks receptor tyrosine-kinase and cyclin kinase pathways, might be of interest. Studies in cancer models suggest that sunitinib might also modulate autophagy, which is dysregulated in our models of Tat-induced neurotoxicity. We evaluated the efficacy of sunitinib to promote autophagy in the CNS and ameliorate neurodegeneration using LC3-GFP-expressing neuronal cells challenged with low concentrations of Tat and using inducible Tat transgenic mice. In neuronal cultures challenged with low levels of Tat, sunitinib increased markers of autophagy such as LC3-II and reduced p62 accumulation in a dose-dependent manner. In vivo, sunitinib treatment restored LC3-II, p62, and endophilin B1 (EndoB1) levels in doxycycline-induced Tat transgenic mice. Moreover, in these animals, sunitinib reduced the hyperactivation of CDK5, tau hyperphosphorylation, and p35 cleavage to p25. Restoration of CDK5 and autophagy were associated with reduced neurodegeneration and behavioral alterations. Alterations in autophagy in the Tat tg mice were associated with reduced levels of a CDK5 substrate, EndoB1, and levels of total EndoB1 were normalized by sunitinib treatment. We conclude that sunitinib might ameliorate Tat-mediated autophagy alterations and may decrease neurodegeneration in aging patients with HAND.

Keywords

Autophagy HIV-1 In vivo Sunitinib 

Notes

Acknowledgments

This work was supported by National Institutes of Aging (AG043384 to EM); the National Institutes of Mental Health (MH062962 to EM), MH5974 and MH83506 to Igor Grant; and the National Institute for Neurological Disorders and Stroke (1F32NS083426-01 to JF).

Author contributions

JF, JM, CO, AA, BS, WW, JF, ER, JJH, and EM performed experiments. EM analyzed data. CO and EM wrote the paper. All authors provided comments on the initial and final drafts of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Journal of NeuroVirology, Inc. 2017

Authors and Affiliations

  • Jerel A. Fields
    • 1
  • Jeff Metcalf
    • 2
  • Cassia Overk
    • 2
  • Anthony Adame
    • 2
  • Brian Spencer
    • 2
  • Wolfgang Wrasidlo
    • 2
  • Jazmin Florio
    • 2
  • Edward Rockenstein
    • 2
  • Johnny J. He
    • 3
  • Eliezer Masliah
    • 1
    • 2
    Email author
  1. 1.Department of PathologyUniversity of California San DiegoLa JollaUSA
  2. 2.Department of NeurosciencesUniversity of California San DiegoLa JollaUSA
  3. 3.Department of Cell Biology and ImmunologyUniversity of North Texas Health Science CenterFort WorthUSA

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