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Functional impact of HIV-1 Tat on cells of the CNS and its role in HAND

Cellular and Molecular Life Sciences volume 77, pages 5079–5099 (2020)Cite this article

Abstract

Human immunodeficiency virus type 1 (HIV-1) transactivator of transcription (Tat) is a potent mediator involved in the development of HIV-1-associated neurocognitive disorders (HAND). Tat is expressed even in the presence of antiretroviral therapy (ART) and is able to enter the central nervous system (CNS) through a variety of ways, where Tat can interact with microglia, astrocytes, brain microvascular endothelial cells, and neurons. The presence of low concentrations of extracellular Tat alone has been shown to lead to dysregulated gene expression, chronic cell activation, inflammation, neurotoxicity, and structural damage in the brain. The reported effects of Tat are dependent in part on the specific HIV-1 subtype and amino acid length of Tat used. HIV-1 subtype B Tat is the most common subtype in North American and therefore, most studies have been focused on subtype B Tat; however, studies have shown many genetic, biologic, and pathologic differences between HIV subtype B and subtype C Tat. This review will focus primarily on subtype B Tat where the full-length protein is 101 amino acids, but will also consider variants of Tat, such as Tat 72 and Tat 86, that have been reported to exhibit a number of distinctive activities with respect to mediating CNS damage and neurotoxicity.

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Acknowledgements

The authors would like to acknowledge BioRender. The software was used to help create Figs. 3 and 4 using the standard academic license held by Dr. Nonnemacher.

Funding

The authors were funded in part by the Public Health Service, National Institutes of Health, through grants from the National Institute of Neurological Disorders and Stroke (NINDS) R01 NS089435 (PI, Michael R. Nonnemacher), the NIMH Comprehensive NeuroAIDS Center (CNAC) P30 MH092177 (Kamel Khalili, PI; Brian Wigdahl, PI of the Drexel subcontract involving the Clinical and Translational Research Support Core) and under the Ruth L. Kirschstein National Research Service Award T32 MH079785 (PI, Kamel Khalili and Tricia Burdo; with Brian Wigdahl serving as the PI of the Drexel University College of Medicine component and Olimpia Meucci as Co-Director). The contents of the paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

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  1. Department of Microbiology and Immunology, Drexel University College of Medicine, 245 N. 15th St, Philadelphia, PA, 19102, USA

    Jamie Marino, Monique E. Maubert, Anthony R. Mele, Cassandra Spector, Brian Wigdahl & Michael R. Nonnemacher

  2. Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA, USA

    Jamie Marino, Monique E. Maubert, Anthony R. Mele, Cassandra Spector, Brian Wigdahl & Michael R. Nonnemacher

  3. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    Brian Wigdahl

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  1. Jamie Marino
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Marino, J., Maubert, M.E., Mele, A.R. et al. Functional impact of HIV-1 Tat on cells of the CNS and its role in HAND. Cell. Mol. Life Sci. 77, 5079–5099 (2020). https://doi.org/10.1007/s00018-020-03561-4

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  • DOI: https://doi.org/10.1007/s00018-020-03561-4

Keywords

  • HIV-1 tat
  • CNS
  • Neurotoxicity
  • HAND
  • Blood–brain barrier