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Endolysosome iron restricts Tat-mediated HIV-1 LTR transactivation by increasing HIV-1 Tat oligomerization and β-catenin expression

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Abstract

HIV-1 transactivator of transcription (Tat) protein is required for HIV-1 replication, and it has been implicated in the pathogenesis of HIV-1-associated neurocognitive disorder (HAND). HIV-1 Tat can enter cells via receptor-mediated endocytosis where it can reside in endolysosomes; upon its escape from these acidic organelles, HIV-1 Tat can enter the cytosol and nucleus where it activates the HIV-1 LTR promoter. Although it is known that HIV-1 replication is affected by the iron status of people living with HIV-1 (PLWH), very little is known about how iron affects HIV-1 Tat activation of the HIV-1 LTR promoter. Because HIV-1 proteins de-acidify endolysosomes and endolysosome de-acidification affects subcellular levels and actions of iron, we tested the hypothesis that the endolysosome pool of iron is sufficient to affect Tat-induced HIV-1 LTR transactivation. Ferric (Fe3+) and ferrous (Fe2+) iron both restricted Tat-mediated HIV-1 LTR transactivation. Chelation of endolysosome iron with deferoxamine (DFO) and 2–2 bipyridyl, but not chelation of cytosolic iron with deferiprone and deferasirox, significantly enhanced Tat-mediated HIV-1 LTR transactivation. In the presence of iron, HIV-1 Tat increasingly oligomerized and DFO prevented the oligomerization. DFO also reduced protein expression levels of the HIV-1 restriction agent beta-catenin in the cytosol and nucleus. These findings suggest that DFO increases HIV-1 LTR transactivation by increasing levels of the more active dimeric form of Tat relative to the less active oligomerized form of Tat, increasing the escape of dimeric Tat from endolysosomes, and/or reducing beta-catenin protein expression levels. Thus, intracellular iron might play a significant role in regulating HIV-1 replication, and these findings raise cautionary notes for chelation therapies in PLWH.

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Funding

This study was funded by the National Institute of General Medical Sciences (P30GM100329, U54GM115458), the National Institute of Mental Health (R01MH100972, R01MH105329, R01MH119000), the National Institute of Neurological Diseases and Stroke (2R01NS065957), and the National Institute of Drug Abuse (2R01DA032444).

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Authors and Affiliations

  1. Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203, USA

    Nabab Khan, Peter W. Halcrow, Leo K. Lakpa, Xuesong Chen & Jonathan D. Geiger

  2. King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia

    Mohd Rehan

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  1. Nabab Khan
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  2. Peter W. Halcrow
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  3. Leo K. Lakpa
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  4. Mohd Rehan
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  5. Xuesong Chen
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  6. Jonathan D. Geiger
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Corresponding author

Correspondence to Jonathan D. Geiger.

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Although the University of North Dakota Animal Care and Use Committee is adherent with the Guide for the Care and Use of Laboratory Animals (NIH publication number 80–23), no animal studies were conducted as part of this work.

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Khan, N., Halcrow, P.W., Lakpa, L.K. et al. Endolysosome iron restricts Tat-mediated HIV-1 LTR transactivation by increasing HIV-1 Tat oligomerization and β-catenin expression. J. Neurovirol. 27, 755–773 (2021). https://doi.org/10.1007/s13365-021-01016-5

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  • DOI: https://doi.org/10.1007/s13365-021-01016-5

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