HIV-1 Tat alters neuronal autophagy by modulating autophagosome fusion to the lysosome: implications for HIV-associated neurocognitive disorders.

TitleHIV-1 Tat alters neuronal autophagy by modulating autophagosome fusion to the lysosome: implications for HIV-associated neurocognitive disorders.
Publication TypeJournal Article
Year of Publication2015
AuthorsFields, J, Dumaop, W, Eleuteri, S, Elueteri, S, Campos, S, Serger, E, Trejo, M, Kosberg, K, Adame, A, Spencer, B, Rockenstein, E, He, JJ, Masliah, E
JournalJ Neurosci
Volume35
Issue5
Pagination1921-38
Date Published2015 Feb 4
ISSN1529-2401
KeywordsAIDS Dementia Complex, Animals, Autophagy, Cell Line, Tumor, Cells, Cultured, HIV-1, Lysosomal-Associated Membrane Protein 2, Lysosomes, Mice, Neurons, Phagosomes, Protein Binding, Rats, tat Gene Products, Human Immunodeficiency Virus
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.

DOI10.1523/JNEUROSCI.3207-14.2015
Alternate JournalJ. Neurosci.
PubMed ID25653352
PubMed Central IDPMC4315828
Grant List1F32NS083426-01 / NS / NINDS NIH HHS / United States
AG043384 / AG / NIA NIH HHS / United States
MH062962 / MH / NIMH NIH HHS / United States
MH5974 / MH / NIMH NIH HHS / United States
MH83506 / MH / NIMH NIH HHS / United States
P30 MH062512 / MH / NIMH NIH HHS / United States
R01 AG043384 / AG / NIA NIH HHS / United States
U24 MH100928 / MH / NIMH NIH HHS / United States