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Genetic variation and function of the HIV-1 Tat protein

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Abstract

Human immunodeficiency virus type 1 (HIV-1) encodes a transactivator of transcription (Tat) protein, which has several functions that promote viral replication, pathogenesis, and disease. Amino acid variation within Tat has been observed to alter the functional properties of Tat and, depending on the HIV-1 subtype, may produce Tat phenotypes differing from viruses’ representative of each subtype and commonly used in in vivo and in vitro experimentation. The molecular properties of Tat allow for distinctive functional activities to be determined such as the subcellular localization and other intracellular and extracellular functional aspects of this important viral protein influenced by variation within the Tat sequence. Once Tat has been transported into the nucleus and becomes engaged in transactivation of the long terminal repeat (LTR), various Tat variants may differ in their capacity to activate viral transcription. Post-translational modification patterns based on these amino acid variations may alter interactions between Tat and host factors, which may positively or negatively affect this process. In addition, the ability of HIV-1 to utilize or not utilize the transactivation response (TAR) element within the LTR, based on genetic variation and cellular phenotype, adds a layer of complexity to the processes that govern Tat-mediated proviral DNA-driven transcription and replication. In contrast, cytoplasmic or extracellular localization of Tat may cause pathogenic effects in the form of altered cell activation, apoptosis, or neurotoxicity. Tat variants have been shown to differentially induce these processes, which may have implications for long-term HIV-1-infected patient care in the antiretroviral therapy era. Future studies concerning genetic variation of Tat with respect to function should focus on variants derived from HIV-1-infected individuals to efficiently guide Tat-targeted therapies and elucidate mechanisms of pathogenesis within the global patient population.

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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, Jay Rappaport; 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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Authors and Affiliations

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

    Cassandra Spector, Anthony R. Mele, 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

    Cassandra Spector, Anthony R. Mele, Brian Wigdahl & Michael R. Nonnemacher

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

    Brian Wigdahl & Michael R. Nonnemacher

Authors
  1. Cassandra Spector
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  2. Anthony R. Mele
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  3. Brian Wigdahl
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  4. Michael R. Nonnemacher
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Corresponding author

Correspondence to Michael R. Nonnemacher.

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Edited by: Roberto F. Speck.

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Spector, C., Mele, A.R., Wigdahl, B. et al. Genetic variation and function of the HIV-1 Tat protein. Med Microbiol Immunol 208, 131–169 (2019). https://doi.org/10.1007/s00430-019-00583-z

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  • DOI: https://doi.org/10.1007/s00430-019-00583-z

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