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


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.


Autophagy HIV-1 In vivo Sunitinib 



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.


  1. Achim CL, Adame A, Dumaop W, Everall IP, Masliah E (2009) Increased accumulation of intraneuronal amyloid beta in HIV-infected patients. J NeuroImmune Pharmacol 4:190–199CrossRefPubMedPubMedCentralGoogle Scholar
  2. Alirezaei M, Kiosses WB, Flynn CT, Brady NR, Fox HS (2008a) Disruption of neuronal autophagy by infected microglia results in neurodegeneration. PLoS One 3:e2906CrossRefPubMedPubMedCentralGoogle Scholar
  3. Alirezaei M, Kiosses WB, Fox HS (2008b) Decreased neuronal autophagy in HIV dementia: a mechanism of indirect neurotoxicity. Autophagy 4:963–966CrossRefPubMedPubMedCentralGoogle Scholar
  4. Avraham HK, Jiang S, Fu Y, Rockenstein E, Makriyannis A, Wood J, Wang L, Masliah E, Avraham S (2015) Impaired neurogenesis by HIV-1-Gp120 is rescued by genetic deletion of fatty acid amide hydrolase enzyme. Br J Pharmacol 172:4603–4614CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bachani M, Sacktor N, McArthur JC, Nath A, Rumbaugh J (2013) Detection of anti-tat antibodies in CSF of individuals with HIV-associated neurocognitive disorders. J Neurovirol 19:82–88CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bruno AP, De Simone FI, Iorio V, De Marco M, Khalili K, Sariyer IK, Capunzo M, Nori SL, Rosati A (2014) HIV-1 tat protein induces glial cell autophagy through enhancement of BAG3 protein levels. Cell Cycle 13:3640–3644CrossRefPubMedPubMedCentralGoogle Scholar
  7. Budka H, Costanzi G, Cristina S, Lechi A, Parravicini C, Trabattoni R, Vago L (1987) Brain pathology induced by infection with the human immunodeficiency virus (HIV). A histological, immunocytochemical, and electron microscopical study of 100 autopsy cases. Acta Neuropathol(Berl) 75:185–198CrossRefGoogle Scholar
  8. Cherner M, Cysique L, Heaton RK, Marcotte TD, Ellis RJ, Masliah E, Grant I (2007) Neuropathologic confirmation of definitional criteria for human immunodeficiency virus-associated neurocognitive disorders. J Neurovirol 13:23–28CrossRefPubMedGoogle Scholar
  9. Clifford DB, Ances BM (2013) HIV-associated neurocognitive disorder. Lancet Infect Dis 13:976–986CrossRefPubMedPubMedCentralGoogle Scholar
  10. Crews L, Spencer B, Desplats P, Patrick C, Paulino A, Rockenstein E, Hansen L, Adame A, Galasko D, Masliah E (2010) Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PLoS One 5:e9313CrossRefPubMedPubMedCentralGoogle Scholar
  11. Cuervo AM (2004) Autophagy: in sickness and in health. Trends Cell Biol 14:70–77CrossRefPubMedGoogle Scholar
  12. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:1292–1295CrossRefPubMedGoogle Scholar
  13. Ellis R, Langford D, Masliah E (2007) HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci 8:33–44CrossRefPubMedGoogle Scholar
  14. Ertmer A, Huber V, Gilch S, Yoshimori T, Erfle V, Duyster J, Elsasser HP, Schatzl HM (2007) The anticancer drug imatinib induces cellular autophagy. Leukemia 21:936–942PubMedGoogle Scholar
  15. Faivre S, Demetri G, Sargent W, Raymond E (2007) Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 6:734–745CrossRefPubMedGoogle Scholar
  16. Fields J, Dumaop W, Adame A, Ellis RJ, Letendre S, Grant I, Masliah E (2013a) Alterations in the levels of vesicular trafficking proteins involved in HIV replication in the brains and CSF of patients with HIV-associated neurocognitive disorders. J NeuroImmune Pharmacol 8:1197–1209CrossRefPubMedPubMedCentralGoogle Scholar
  17. Fields J, Dumaop W, Rockenstein E, Mante M, Spencer B, Grant I, Ellis R, Letendre S, Patrick C, Adame A, Masliah E (2013b) Age-dependent molecular alterations in the autophagy pathway in HIVE patients and in a gp120 tg mouse model: reversal with beclin-1 gene transfer. Journal of neurovirology 19:89–101CrossRefPubMedPubMedCentralGoogle Scholar
  18. Fields J, Dumaop W, Eleuteri S, Campos S, Serger E, Trejo M, Kosberg K, Adame A, Spencer B, Rockenstein E, He JJ, Masliah E (2015a) HIV-1 tat alters neuronal autophagy by modulating autophagosome fusion to the lysosome: implications for HIV-associated neurocognitive disorders. The Journal of neuroscience : the official journal of the Society for Neuroscience 35:1921–1938CrossRefGoogle Scholar
  19. Fields JA, Dumaop W, Crews L, Adame A, Spencer B, Metcalf J, He J, Rockenstein E, Masliah E (2015b) Mechanisms of HIV-1 tat neurotoxicity via CDK5 translocation and hyper-activation: role in HIV-associated neurocognitive disorders. Curr HIV Res 13:43–54CrossRefPubMedPubMedCentralGoogle Scholar
  20. Fields JA, Serger E, Campos S, Divakaruni AS, Kim C, Smith K, Trejo M, Adame A, Spencer B, Rockenstein E, Murphy AN, Ellis RJ, Letendre S, Grant I, Masliah E (2016) HIV alters neuronal mitochondrial fission/fusion in the brain during HIV-associated neurocognitive disorders. Neurobiol Dis 86:154–169CrossRefPubMedGoogle Scholar
  21. Gendelman HE, Persidsky Y, Ghorpade A, Limoges J, Stins M, Fiala M, Morrisett R (1997) The neuropathogenesis of the AIDS dementia complex. AIDS 11(Suppl A):S35–S45PubMedGoogle Scholar
  22. Gotink KJ, Verheul HM (2010) Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis 13:1–14CrossRefPubMedGoogle Scholar
  23. Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C, Vaida F, Ellis RJ, Letendre SL, Marcotte TD, Atkinson JH, Rivera-Mindt M, Vigil OR, Taylor MJ, Collier AC, Marra CM, Gelman BB, McArthur JC, Morgello S, Simpson DM, McCutchan JA, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER study. Neurology 75:2087–2096CrossRefPubMedPubMedCentralGoogle Scholar
  24. Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, Leblanc S, Corkran SH, Duarte NA, Clifford DB, Woods SP, Collier AC, Marra CM, Morgello S, Mindt MR, Taylor MJ, Marcotte TD, Atkinson JH, Wolfson T, Gelman BB, McArthur JC, Simpson DM, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I (2011) HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. Journal of neurovirology 17:3–16CrossRefPubMedGoogle Scholar
  25. Hui L, Chen X, Haughey NJ, Geiger JD (2012) Role of endolysosomes in HIV-1 tat-induced neurotoxicity. ASN neuro 4:243–252CrossRefPubMedGoogle Scholar
  26. Joska JA, Gouse H, Paul RH, Stein DJ, Flisher AJ (2010) Does highly active antiretroviral therapy improve neurocognitive function? A systematic review. J Neurovirol 16:101–114CrossRefPubMedGoogle Scholar
  27. Kaul M, Lipton SA (2006) Mechanisms of neuronal injury and death in HIV-1 associated dementia. Curr HIV Res 4:307–318CrossRefPubMedGoogle Scholar
  28. Kim BO, Liu Y, Ruan Y, Xu ZC, Schantz L, He JJ (2003) Neuropathologies in transgenic mice expressing human immunodeficiency virus type 1 tat protein under the regulation of the astrocyte-specific glial fibrillary acidic protein promoter and doxycycline. Am J Pathol 162:1693–1707CrossRefPubMedPubMedCentralGoogle Scholar
  29. Kyei GB, Dinkins C, Davis AS, Roberts E, Singh SB, Dong C, Wu L, Kominami E, Ueno T, Yamamoto A, Federico M, Panganiban A, Vergne I, Deretic V (2009) Autophagy pathway intersects with HIV-1 biosynthesis and regulates viral yields in macrophages. J Cell Biol 186:255–268CrossRefPubMedPubMedCentralGoogle Scholar
  30. Lashuel HA, Overk CR, Oueslati A, Masliah E (2013) The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci 14:38–48CrossRefPubMedPubMedCentralGoogle Scholar
  31. Lee MH, Amin ND, Venkatesan A, Wang T, Tyagi R, Pant HC, Nath A (2013) Impaired neurogenesis and neurite outgrowth in an HIV-gp120 transgenic model is reversed by exercise via BDNF production and Cdk5 regulation. Journal of neurovirology 19:418–431CrossRefPubMedPubMedCentralGoogle Scholar
  32. Lin CI, Whang EE, Lorch JH, Ruan DT (2012) Autophagic activation potentiates the antiproliferative effects of tyrosine kinase inhibitors in medullary thyroid cancer. Surgery 152:1142–1149CrossRefPubMedGoogle Scholar
  33. Lipton SA (1994) AIDS-related dementia and calcium homeostasis. Ann N Y Acad Sci 747:205–224CrossRefPubMedGoogle Scholar
  34. Lipton SA, Rosenberg PA (1994) Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 330:613–622CrossRefPubMedGoogle Scholar
  35. Masliah E, Alford M, Adame A, Rockenstein E, Galasko D, Salmon D, Hansen LA, Thal LJ (2003) Abeta1-42 promotes cholinergic sprouting in patients with AD and Lewy body variant of AD. Neurology 61:206–211CrossRefPubMedGoogle Scholar
  36. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124CrossRefPubMedGoogle Scholar
  37. Nath A (2002) Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia. J Infect Dis 186(Suppl 2):S193–S198CrossRefPubMedGoogle Scholar
  38. Nath A, Haughey NJ, Jones M, Anderson C, Bell JE, Geiger JD (2000) Synergistic neurotoxicity by human immunodeficiency virus proteins tat and gp120: protection by memantine. Ann Neurol 47:186–194CrossRefPubMedGoogle Scholar
  39. Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM (2005) Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 64:113–122CrossRefPubMedGoogle Scholar
  40. Norman JP, Perry SW, Reynolds HM, Kiebala M, De Mesy Bentley KL, Trejo M, Volsky DJ, Maggirwar SB, Dewhurst S, Masliah E, Gelbard HA (2008) HIV-1 tat activates neuronal ryanodine receptors with rapid induction of the unfolded protein response and mitochondrial hyperpolarization. PLoS One 3:e3731CrossRefPubMedPubMedCentralGoogle Scholar
  41. O’Farrell AM, Foran JM, Fiedler W, Serve H, Paquette RL, Cooper MA, Yuen HA, Louie SG, Kim H, Nicholas S, Heinrich MC, Berdel WE, Bello C, Jacobs M, Scigalla P, Manning WC, Kelsey S, Cherrington JM (2003) An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clinical cancer research : an official journal of the American Association for Cancer Research 9:5465–5476Google Scholar
  42. Overk CR, Cartier A, Shaked G, Rockenstein E, Ubhi K, Spencer B, Price DL, Patrick C, Desplats P, Masliah E (2014) Hippocampal neuronal cells that accumulate alpha-synuclein fragments are more vulnerable to Abeta oligomer toxicity via mGluR5--implications for dementia with Lewy bodies. Mol Neurodegener 9:18CrossRefPubMedPubMedCentralGoogle Scholar
  43. Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S, Spencer B, Rockenstein E, Levine B, Wyss-Coray T (2008) The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Investig 118:2190–2199PubMedPubMedCentralGoogle Scholar
  44. Ranki A, Nyberg M, Ovod V, Haltia M, Elovaara I, Raininko R, Haapasalo H, Krohn K (1995) Abundant expression of HIV Nef and Rev proteins in brain astrocytes in vivo is associated with dementia. AIDS 9:1001–1008CrossRefPubMedGoogle Scholar
  45. Rempel HC, Pulliam L (2005) HIV-1 tat inhibits neprilysin and elevates amyloid beta. AIDS 19:127–135CrossRefPubMedGoogle Scholar
  46. Richard J, Pham TN, Ishizaka Y, Cohen EA (2013) Viral protein R upregulates expression of ULBP2 on uninfected bystander cells during HIV-1 infection of primary CD4+ T lymphocytes. Virology 443:248–256CrossRefPubMedPubMedCentralGoogle Scholar
  47. Rohn TT, Wirawan E, Brown RJ, Harris JR, Masliah E, Vandenabeele P (2011) Depletion of beclin-1 due to proteolytic cleavage by caspases in the Alzheimer’s disease brain. Neurobiol Dis 43:68–78CrossRefPubMedGoogle Scholar
  48. Rom S, Pacifici M, Passiatore G, Aprea S, Waligorska A, Del Valle L, Peruzzi F (2011) HIV-1 tat binds to SH3 domains: cellular and viral outcome of tat/Grb2 interaction. Biochim Biophys Acta 1813:1836–1844CrossRefPubMedPubMedCentralGoogle Scholar
  49. Saito Y, Sharer L, Epstein L, Michaels J, Mintz M, Louder M, Golding K, Cvetkovich T, Blumberg B (1994) Overexpression of nef as a marker for restricted HIV-1 infection of astrocytes in postmortem pediatric central nervous tissues. Neurology 44:474–481CrossRefPubMedGoogle Scholar
  50. Santoni M, Amantini C, Morelli MB, Liberati S, Farfariello V, Nabissi M, Bonfili L, Eleuteri AM, Mozzicafreddo M, Burattini L, Berardi R, Cascinu S, Santoni G (2013) Pazopanib and sunitinib trigger autophagic and non-autophagic death of bladder tumour cells. Br J Cancer 109:1040–1050CrossRefPubMedPubMedCentralGoogle Scholar
  51. Schenk D, Masliah E, Buttini M, Tamie CJ, Rockenstein EM, Game K (2011). Prevention and Treatment of synucleinopathic and amyloidogenic disease. The Regents of the University of California, Elan Pharmaceuticals, Inc.Google Scholar
  52. Schueneman AJ, Himmelfarb E, Geng L, Tan J, Donnelly E, Mendel D, McMahon G, Hallahan DE (2003) SU11248 maintenance therapy prevents tumor regrowth after fractionated irradiation of murine tumor models. Cancer Res 63:4009–4016PubMedGoogle Scholar
  53. Scott JC, Woods SP, Carey CL, Weber E, Bondi MW, Grant I (2011) Neurocognitive consequences of HIV infection in older adults: an evaluation of the "cortical" hypothesis. AIDS Behav 15:1187–1196CrossRefPubMedGoogle Scholar
  54. Shah K, Lahiri DK (2014) Cdk5 activity in the brain—multiple paths of regulation. J Cell Sci 127:2391–2400CrossRefPubMedPubMedCentralGoogle Scholar
  55. Spencer B, Potkar R, Trejo M, Rockenstein E, Patrick C, Gindi R, Adame A, Wyss-Coray T, Masliah E (2009) Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson’s and Lewy body diseases. The Journal of neuroscience : the official journal of the Society for Neuroscience 29:13578–13588CrossRefGoogle Scholar
  56. Takahashi Y, Meyerkord CL, Wang HG (2009) Bif-1/endophilin B1: a candidate for crescent driving force in autophagy. Cell Death Differ 16:947–955CrossRefPubMedPubMedCentralGoogle Scholar
  57. Takeuchi H, Kanzawa T, Kondo Y, Kondo S (2004) Inhibition of platelet-derived growth factor signalling induces autophagy in malignant glioma cells. Br J Cancer 90:1069–1075CrossRefPubMedPubMedCentralGoogle Scholar
  58. Toborek M, Lee YW, Pu H, Malecki A, Flora G, Garrido R, Hennig B, Bauer HC, Nath A (2003) HIV-tat protein induces oxidative and inflammatory pathways in brain endothelium. J Neurochem 84:169–179CrossRefPubMedGoogle Scholar
  59. Valcour V, Shiramizu B (2004) HIV-associated dementia, mitochondrial dysfunction, and oxidative stress. Mitochondrion 4:119–129CrossRefPubMedGoogle Scholar
  60. Var SR, Day TR, Vitomirov A, Smith DM, Soontornniyomkij V, Moore DJ, Achim CL, Mehta SR, Perez-Santiago J (2016) Mitochondrial injury and cognitive function in HIV infection and methamphetamine use. AIDS 30:839–848CrossRefPubMedGoogle Scholar
  61. Wang W, Perovic I, Chittuluru J, Kaganovich A, Nguyen LT, Liao J, Auclair JR, Johnson D, Landeru A, Simorellis AK, Ju S, Cookson MR, Asturias FJ, Agar JN, Webb BN, Kang C, Ringe D, Petsko GA, Pochapsky TC, Hoang QQ (2011) A soluble alpha-synuclein construct forms a dynamic tetramer. Proc Natl Acad Sci U S A 108:17797–17802CrossRefPubMedPubMedCentralGoogle Scholar
  62. Wang DB, Uo T, Kinoshita C, Sopher BL, Lee RJ, Murphy SP, Kinoshita Y, Garden GA, Wang HG, Morrison RS (2014) Bax interacting factor-1 promotes survival and mitochondrial elongation in neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 34:2674–2683CrossRefGoogle Scholar
  63. Wang DB, Kinoshita Y, Kinoshita C, Uo T, Sopher BL, Cudaback E, Keene CD, Bilousova T, Gylys K, Case A, Jayadev S, Wang HG, Garden GA, Morrison RS (2015) Loss of endophilin-B1 exacerbates Alzheimer’s disease pathology. Brain : a journal of neurology 138:2005–2019CrossRefGoogle Scholar
  64. Wiley C, Achim C (1994) HIV encephalitis is the pathologic correlate of dementia in AIDS. AnnNeurol 36:673–676Google Scholar
  65. Wong AS, Lee RH, Cheung AY, Yeung PK, Chung SK, Cheung ZH, Ip NY (2011) Cdk5-mediated phosphorylation of endophilin B1 is required for induced autophagy in models of Parkinson’s disease. Nat Cell Biol 13:568–579CrossRefPubMedGoogle Scholar
  66. Wrasidlo W, Crews LA, Tsigelny IF, Stocking E, Kouznetsova VL, Price D, Paulino A, Gonzales T, Overk CR, Patrick C, Rockenstein E, Masliah E (2014) Neuroprotective effects of the anti-cancer drug sunitinib in models of HIV neurotoxicity suggests potential for the treatment of neurodegenerative disorders. Br J Pharmacol 171:5757–5773CrossRefPubMedPubMedCentralGoogle Scholar
  67. Zhou D, Masliah E, Spector SA (2011) Autophagy is increased in postmortem brains of persons with HIV-1-associated encephalitis. J Infect Dis 203:1647–1657CrossRefPubMedPubMedCentralGoogle Scholar

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

Personalised recommendations