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Defining the roles for Vpr in HIV-1-associated neuropathogenesis

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Abstract

It is increasingly evident that the human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) has a unique role in neuropathogenesis. Its ability to induce G2/M arrest coupled with its capacity to increase viral gene transcription gives it a unique role in sustaining viral replication and aiding in the establishment and maintenance of a systemic infection. The requirement of Vpr for HIV-1 infection and replication in cells of monocytic origin (a key lineage of cells involved in HIV-1 neuroinvasion) suggests an important role in establishing and sustaining infection in the central nervous system (CNS). Contributions of Vpr to neuropathogenesis can be expanded further through (i) naturally occurring HIV-1 sequence variation that results in functionally divergent Vpr variants; (ii) the dual activities of Vpr as a intracellular protein delivered and expressed during HIV-1 infection and as an extracellular protein that can act on neighboring, uninfected cells; (iii) cell type-dependent consequences of Vpr expression and exposure, including cell cycle arrest, metabolic dysregulation, and cytotoxicity; and (iv) the effects of Vpr on exosome-based intercellular communication in the CNS. Revealing that the effects of this pleiotropic viral protein is an essential part of a greater understanding of HIV-1-associated pathogenesis and potential approaches to treating and preventing disease caused by HIV-1 infection.

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Acknowledgments

This work was partially supported by P30 MH092177 Comprehensive NeuroAIDS Center (CNAC, Program Director: Kamel Khalili, Brian Wigdahl, PI of the Drexel subcontract). These studies were also supported by the Public Health Service, National Institutes of Health, through grants from the National Institute of Neurological Disorders and Stroke (NS32092 and NS46263), the National Institute of Drug Abuse (DA19807; Dr. Brian Wigdahl, Principal Investigator), and the National Institute of Mental Health under the Ruth L. Kirschstein National Research Service Award (5T32MH079785; Jay Rappaport, PI, Brian Wigdahl, PI of the Drexel subcontract). The contents of the paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Dr. Michael Nonnemacher was supported in part by the Public Health Service, National Institutes of Health, through a grant from the National Institute of Neurological Disorders and Stroke (NS089435) and faculty development funds provided by the Department of Microbiology and Immunology and the Institute for Molecular Medicine and Infectious Disease. Dr. Fred Krebs was supported by a developmental grant awarded by CNAC.

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  1. Department of Microbiology and Immunology, and Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Mail stop 1013-A, 245 N. 15th Street, Philadelphia, PA, 19102, USA

    Tony James, Michael R. Nonnemacher, Brian Wigdahl & Fred C. Krebs

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

    Brian Wigdahl

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  1. Tony James
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Correspondence to Fred C. Krebs.

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James, T., Nonnemacher, M.R., Wigdahl, B. et al. Defining the roles for Vpr in HIV-1-associated neuropathogenesis. J. Neurovirol. 22, 403–415 (2016). https://doi.org/10.1007/s13365-016-0436-5

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