HIV-1 Tat Alters Neuronal Autophagy by Modulating Autophagosome Fusion to the Lysosome: Implications for HIV-Associated Neurocognitive Disorders
Open accessAbstract
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.
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HIV-TAT can damage lysosome function in microglia and in neuron.
“HIV-TAT can damage lysosome function in microglia and in neuron [46, 75].”
From HIV-TAT dysregulates microglial lipid metabolism through SREBP2/miR-124 axis: Implication of lipid droplet accumulation microglia in NeuroHIV (2025) · cites this paper as [75]
The Introduction and Discussion report that Tat alters autophagosome–lysosome fusion in neurons and may cause deleterious, aberrant degradation. The paper does not establish that Tat damages lysosome function in microglia; its mention of microglial supernatant concerns other HIV-related effects. Thus it supports the neuronal part of the sentence, not the microglial part. (LLM, conf=0.86)
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- Authors
- Fields, J., Dumaop, W., Elueteri, S., Campos, S., Serger, E., Trejo, M., Kosberg, K., Adame, A., Spencer, B., Rockenstein, E., He, J. J., & Masliah, E.
- Affiliations
- University of California San Diego (US)
- University of North Texas Health Science Center (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2015-02-04
- Volume
- 35
- Issue
- 5
- Pages
- 1921-1938
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4315828
- OpenAlex
- W2050541584
- Cited by
- 133
- References
- 64
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 11 · 2023: 6 · 2022: 12 · 2021: 14 · 2020: 21 · 2019: 15 · 2018: 15 · 2017: 13 · 2016: 9 · 2015: 4
- FWCI
- 10.72
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG043384, R01AG043384)
- National Institute of Mental Health (U01MH083506, R01MH062962, U24MH100928, U01MH083500, MH5974, MH83506, MH062962, U24MH100929)
- National Institute of Neurological Disorders and Stroke (F32NS083426)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- HIV-1 Tat protein, neuronal autophagy, autophagosome-lysosome fusion, HIV-associated neurocognitive disorders, neurodegeneration, LAMP2A, LC3-II, p62, bafilomycin A1, rapamycin, neurotoxicity
- MeSH terms
- Animals, Autophagy, Cells, Cultured, Lysosomes, Neurons, Phagosomes, Protein Binding, HIV-1, AIDS Dementia Complex, Cell Line, Tumor, Mice, Rats, Lysosomal-Associated Membrane Protein 2, tat Gene Products, Human Immunodeficiency Virus
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