Functional impact of HIV-1 Tat on cells of the CNS and its role in HAND
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Cellular and Molecular Life Sciences
REVIEW
Functional impact of HIV‑1 Tat on cells of the CNS and its role in HAND Jamie Marino1,2 · Monique E. Maubert1,2 · Anthony R. Mele1,2 · Cassandra Spector1,2 · Brian Wigdahl1,2,3 · Michael R. Nonnemacher1,2 Received: 3 March 2020 / Revised: 8 May 2020 / Accepted: 25 May 2020 © Springer Nature Switzerland AG 2020
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. Keywords HIV-1 tat · CNS · Neurotoxicity · HAND · Blood–brain barrier
Introduction HIV-1 infection is known to involve the seeding of latent viral reservoirs at very early stages of primary infection. Subsequent treatment of infected individuals with life-long suppressive antiretroviral (ART) therapy has been shown to reduce viral burden in the peripheral blood and minimize risk of viral reactivation and possibly expansion of the latent reservoirs. Reactivation of latent reservoirs has been shown in notable cases such as the “Boston patients,” the “Mississippi baby,” and the VISCONTI Cohort in France, which reported viral rebounds after discontinuation of suppressive * Michael R. Nonnemacher [email protected] 1
Department of Microbiology and Immunology, Drexel University College of Medicine, 245 N. 15th St, Philadelphia, PA 19102, USA
2
Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA, USA
3
Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
ART [1–4]. One of the major reservoirs for HIV-1 has been shown to involve the breach of the blood–brain barrier (BBB), which results in the establishment of a reservoir in the central nervous system (CNS) within hours to days after infection, in most cases before ART ha
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