The DOI matches its Crossref record; 64 of the 64 references it cites were found in a registry or an index.
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 [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]
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1 retracted
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“43 software (NIH), as previously described (Crews et al., 2010).”
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In Vivo Gene Delivery and Stable Transduction of Nondividing Cells by a Lentiviral Vector
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“LC3II interaction with SQSTM1 mediates selective recruitment of ubiquitylated proteins to the autophagosome (Pankiv et al., 2007).”
BackgroundHeaton, R. K., Clifford, D. B., Franklin, D. R., Woods, S. P., Ake, C., Vaida, F., Ellis, R. J., Letendre, S. L., Marcotte, T. D., Atkinson, J. H., et al. (2010) · Neurology · doi:10.1212/wnl.0b013e318200d727 · Cited by 2,353 · cited 2×
“Modern treatment regimens result in HIV suppression and immune recovery; however, the prevalence of HIV-associated neurocognitive disorders (HAND) and neurodegeneration (Budka et al., 1987; Wiley and Achim, 1994; Gendelman et al., 1997; Cherner et al., 2007; Heaton et al., 2010) has remained the same or increased (Jos…”
BackgroundImpaired Degradation of Mutant α-Synuclein by Chaperone-Mediated Autophagy
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“Therefore, Tat may interfere with CMA and thereby indirectly increase macroautophagy function as a feedback mechanism to maintain recycling of neuronal components.”
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Nixon, R. A., Wegiel, J., Kumar, A., Yu, W. H., Peterhoff, C., Cataldo, A., & Cuervo, A. M. (2005) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/64.2.113 · Cited by 1,588 · cited 2×
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Cited by
Sorted by citations
Interplay of endoplasmic reticulum stress and autophagy in neurodegenerative disorders
Cai, Y. C., Arikkath, J., Yang, L., Guo, M., Periyasamy, P., & Buch, S. J. (2016) · Autophagy · doi:10.1080/15548627.2015.1121360 · Cited by 259
“8).(182,183) Autophagy dysfunction in HIV patients has also been linked with aging.”
BackgroundTherapeutic targeting of autophagy in neurodegenerative and infectious diseases
Rubinsztein, D. C., Bento, C. F., & Deretic, V. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20150956 · Cited by 202
Sarıbaş, A. S., Cicalese, S. M., Ahooyi, T. M., Khalili, K., Amini, S., & Sariyer, I. K. (2017) · Cell Death and Disease · doi:10.1038/cddis.2016.467 · Cited by 136
Tavera-Mendoza, L. E., Westerling, T., Libby, E., Marusyk, A., Cato, L., Cassani, R., Cameron, L., Ficarro, S. B., Marto, J. A., Klawitter, J., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1615015114 · Cited by 124
“Because autophagosome accumulation is toxic to cells (27, 28), we hypothesized that inducing autophagosome formation with 1,25(OH)2D3 and then blocking autophagosome degradation would be detrimental to cell survival.”
BackgroundBasic science and pathogenesis of ageing with HIV
Lagathu, C., Cossarizza, A., Béréziat, V., Nasi, M., Capeau, J., & Pinti, M. (2017) · AIDS · doi:10.1097/qad.0000000000001441 · Cited by 114
Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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