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Articles, Neurobiology of Disease

HIV-1 Tat Alters Neuronal Autophagy by Modulating Autophagosome Fusion to the Lysosome: Implications for HIV-Associated Neurocognitive Disorders

Jerel Fields, Wilmar Dumaop, Simona Elueteri, Sofia Campos, Elisabeth Serger, Margarita Trejo, Kori Kosberg, Anthony Adame, Brian Spencer, Edward Rockenstein, Johnny J. He and Eliezer Masliah
Journal of Neuroscience 4 February 2015, 35 (5) 1921-1938; DOI: https://doi.org/10.1523/JNEUROSCI.3207-14.2015
Jerel Fields
1Departments of Pathology and
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Wilmar Dumaop
1Departments of Pathology and
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Simona Elueteri
2Neurosciences, University of California San Diego, La Jolla, California 92093-0624 and
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Sofia Campos
2Neurosciences, University of California San Diego, La Jolla, California 92093-0624 and
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  • ORCID record for Sofia Campos
Elisabeth Serger
2Neurosciences, University of California San Diego, La Jolla, California 92093-0624 and
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Margarita Trejo
2Neurosciences, University of California San Diego, La Jolla, California 92093-0624 and
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Kori Kosberg
2Neurosciences, University of California San Diego, La Jolla, California 92093-0624 and
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Anthony Adame
2Neurosciences, University of California San Diego, La Jolla, California 92093-0624 and
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Brian Spencer
2Neurosciences, University of California San Diego, La Jolla, California 92093-0624 and
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Edward Rockenstein
2Neurosciences, University of California San Diego, La Jolla, California 92093-0624 and
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Johnny J. He
3Departments of Cell Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas 76107
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Eliezer Masliah
1Departments of Pathology and
2Neurosciences, University of California San Diego, La Jolla, California 92093-0624 and
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This article has a correction. Please see:

  • Correction: Fields et al., HIV Tat Alters Neuronal Autophagy by Modulating Autophagosome Fusion to the Lysosome: Implications for HIV-Associated Neurocognitive Disorders - May 27, 2015

Abstract

Antiretroviral therapy has increased the life span of HIV+ individuals; however, HIV-associated neurocognitive disorder (HAND) occurrence is increasing in aging HIV patients. Previous studies suggest HIV infection alters autophagy function in the aging CNS and HIV-1 proteins affect autophagy in monocyte-derived cells. Despite these findings, the mechanisms leading to dysregulated autophagy in the CNS remain unclear. Here we sought to determine how HIV Tat dysregulates autophagy in neurons. Tat caused a dose-dependent decrease in autophagosome markers, microtubule-associated protein-1 light chain β II (LC3II), and sequestosome 1(SQSTM1), in a membrane-enriched fraction, suggesting Tat increases autophagic degradation. Bafilomycin A1 increased autophagosome number, LC3II, and SQSTM1 accumulation; Tat cotreatment diminished this effect. Tat had no effect when 3-methyladenine or knockdown of beclin 1 blocked early stages of autophagy. Tat increased numbers of LC3 puncta and resulted in the formation of abnormal autophagosomes in vitro. Likewise, in vivo studies in GFAP-Tat tg mice showed increased autophagosome accumulation in neurons, altered LC3II levels, and neurodegeneration. These effects were reversed by rapamycin treatment. Tat colocalized with autophagosome and lysosomal markers and enhanced the colocalization of autophagosome with lysosome markers. Furthermore, co-IP studies showed that Tat interacts with lysosomal-associated membrane protein 2A (LAMP2A) in vitro and in vivo, and LAMP2A overexpression reduces Tat-induced neurotoxicity. Hence, Tat protein may induce autophagosome and lysosome fusion through interaction with LAMP2A leading to abnormal neuronal autophagy function and dysregulated degradation of critical intracellular components. Therapies targeting Tat-mediated autophagy alterations may decrease neurodegeneration in aging patients with HAND.

  • autophagy
  • HIV
  • LAMP2A
  • Tat
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The Journal of Neuroscience: 35 (5)
Journal of Neuroscience
Vol. 35, Issue 5
4 Feb 2015
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HIV-1 Tat Alters Neuronal Autophagy by Modulating Autophagosome Fusion to the Lysosome: Implications for HIV-Associated Neurocognitive Disorders
Jerel Fields, Wilmar Dumaop, Simona Elueteri, Sofia Campos, Elisabeth Serger, Margarita Trejo, Kori Kosberg, Anthony Adame, Brian Spencer, Edward Rockenstein, Johnny J. He, Eliezer Masliah
Journal of Neuroscience 4 February 2015, 35 (5) 1921-1938; DOI: 10.1523/JNEUROSCI.3207-14.2015

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HIV-1 Tat Alters Neuronal Autophagy by Modulating Autophagosome Fusion to the Lysosome: Implications for HIV-Associated Neurocognitive Disorders
Jerel Fields, Wilmar Dumaop, Simona Elueteri, Sofia Campos, Elisabeth Serger, Margarita Trejo, Kori Kosberg, Anthony Adame, Brian Spencer, Edward Rockenstein, Johnny J. He, Eliezer Masliah
Journal of Neuroscience 4 February 2015, 35 (5) 1921-1938; DOI: 10.1523/JNEUROSCI.3207-14.2015
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Keywords

  • autophagy
  • HIV
  • LAMP2a
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