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      Mechanisms of CNS Viral Seeding by HIV + CD14 + CD16 + Monocytes: Establishment and Reseeding of Viral Reservoirs Contributing to HIV-Associated Neurocognitive Disorders

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          ABSTRACT

          HIV reservoirs persist despite antiretroviral therapy (ART) and are established within a few days after infection. Infected myeloid cells in the central nervous system (CNS) may contribute to the establishment of a CNS viral reservoir. The mature CD14 + CD16 + monocyte subset enters the CNS in response to chemokines, including CCL2. Entry of infected CD14 + CD16 + monocytes may lead to infection of other CNS cells, including macrophages or microglia and astrocytes, and to release of neurotoxic early viral proteins and additional cytokines. This contributes to neuroinflammation and neuronal damage leading to HIV-associated neurocognitive disorders (HAND) in ~50% of HIV-infected individuals despite ART. We examined the mechanisms of monocyte entry in the context of HIV infection and report for the first time that HIV + CD14 + CD16 + monocytes preferentially transmigrate across the blood-brain barrier (BBB). The junctional proteins JAM-A and ALCAM and the chemokine receptor CCR2 are essential to their preferential transmigration across the BBB to CCL2. We show here that JAM-A and ALCAM are increased on HIV + CD14 + CD16 + monocytes compared to their expression on HIV exp CD14 + CD16 + monocytes—cells that are uninfected but exposed to HIV, viral proteins, and inflammatory mediators. Antibodies against JAM-A and ALCAM and the novel CCR2/CCR5 dual inhibitor cenicriviroc prevented or significantly reduced preferential transmigration of HIV + CD14 + CD16 + monocytes. This indicates that JAM-A, ALCAM, and CCR2 may be potential therapeutic targets to block entry of these infected cells into the brain and prevent or reduce the establishment and replenishment of viral reservoirs within the CNS.

          IMPORTANCE

          HIV infects different tissue compartments of the body, including the central nervous system (CNS). This leads to establishment of viral reservoirs within the CNS that mediate neuroinflammation and neuronal damage, contributing to cognitive impairment. Our goal was to examine the mechanisms of transmigration of cells that contribute to HIV infection of the CNS and to continued replenishment of CNS viral reservoirs, to establish potential therapeutic targets. We found that an HIV-infected subset of monocytes, mature HIV + CD14 + CD16 + monocytes, preferentially transmigrates across the blood-brain barrier. This was mediated, in part, by increased junctional proteins JAM-A and ALCAM and chemokine receptor CCR2. We show that the CCR2/CCR5 dual inhibitor cenicriviroc and blocking antibodies against the junctional proteins significantly reduce, and often completely block, the transmigration of HIV + CD14 + CD16 + monocytes. This suggests new opportunities to eliminate infection and seeding or reseeding of viral reservoirs within the CNS, thus reducing neuroinflammation, neuronal damage, and cognitive impairment.

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          Most cited references54

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          The CD14+ CD16+ blood monocytes: their role in infection and inflammation.

          Blood monocyte subpopulations have been defined in man initially, and the two major types of monocytes are the CD14++ CD16- and the CD14+ CD16+ monocytes. These cells have been shown to exhibit distinct phenotype and function, and the CD14+ CD16+ were labeled proinflammatory based on higher expression of proinflammatory cytokines and higher potency in antigen presentation. The current review describes these properties, including the relationship to dendritic cells, and summarizes the host of publications about CD14+ CD16+ monocytes in inflammation and infectious disease in man, all of which suggest a crucial role of these cells in the disease processes. The review also covers the more recent description of homologues of these cells in other model species, which is expected to better define the role of monocyte subsets in disease.
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            Activated leukocyte cell adhesion molecule promotes leukocyte trafficking into the central nervous system.

            Adhesion molecules of the immunoglobulin superfamily are crucial effectors of leukocyte trafficking into the central nervous system. Using a lipid raft-based proteomic approach, we identified ALCAM as an adhesion molecule involved in leukocyte migration across the blood-brain barrier (BBB). ALCAM expressed on BBB endothelium localized together with CD6 on leukocytes and with BBB endothelium transmigratory cups. ALCAM expression on BBB cells was upregulated in active multiple sclerosis and experimental autoimmune encephalomyelitis lesions. Moreover, ALCAM blockade restricted the transmigration of CD4+ lymphocytes and monocytes across BBB endothelium in vitro and in vivo and reduced the severity and delayed the time of onset of experimental autoimmune encephalomyelitis. Our findings indicate an important function for ALCAM in the recruitment of leukocytes into the brain and identify ALCAM as a potential target for the therapeutic dampening of neuroinflammation.
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              The role of junctional adhesion molecules in vascular inflammation.

              Junctional adhesion molecules (JAMs) of the immunoglobulin superfamily are important in the control of vascular permeability and leukocyte transmigration across endothelial-cell surfaces, by engaging in homophilic, heterophilic and lateral interactions. Through their localization on the endothelial-cell surface and expression by platelets, JAMs contribute to adhesive interactions with circulating leukocytes and platelets. Antibody-blocking studies and studies using genetically modified mice have implicated these functions of JAMs in the regulation of leukocyte recruitment to sites of inflammation and ischaemia-reperfusion injury, in growth-factor-mediated angiogenesis, atherogenesis and neointima formation. The comparison of different JAM-family members and animal models, however, shows that the picture remains rather complex. This Review summarizes recent progress and future directions in understanding the role of JAMs as 'gate keepers' in inflammation and vascular pathology.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                mBio
                MBio
                mbio
                mbio
                mBio
                mBio
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                2150-7511
                24 October 2017
                Sep-Oct 2017
                : 8
                : 5
                : e01280-17
                Affiliations
                [a ]Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA
                [b ]Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
                [c ]Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
                [d ]Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
                Harvard School of Public Health
                Author notes
                Address correspondence to Joan W. Berman, joan.berman@ 123456einstein.yu.edu .
                Article
                mBio01280-17
                10.1128/mBio.01280-17
                5654927
                29066542
                5a428823-adfc-43a9-acad-c98eb1a29b91
                Copyright © 2017 Veenstra et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 20 July 2017
                : 27 September 2017
                Page count
                supplementary-material: 1, Figures: 4, Tables: 1, Equations: 0, References: 78, Pages: 15, Words: 10711
                Funding
                Funded by: HHS | National Institutes of Health (NIH) https://doi.org/10.13039/100000002
                Award ID: P30AI124414
                Award Recipient : Joan W. Berman
                Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) https://doi.org/10.13039/100000060
                Award ID: R01AI127142
                Award Recipient : Janice Clements
                Funded by: HHS | NIH | National Center for Advancing Translational Sciences (NCATS) https://doi.org/10.13039/100006108
                Award ID: TL1TR001072
                Award Recipient : Joan W. Berman
                Funded by: HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) https://doi.org/10.13039/100000065
                Award ID: R01NS077869
                Award Recipient : Janice Clements
                Funded by: HHS | NIH | National Institute of Mental Health (NIMH) https://doi.org/10.13039/100000025
                Award ID: R01MH075679
                Award Recipient : Joan W. Berman
                Funded by: HHS | NIH | National Institute of Mental Health (NIMH) https://doi.org/10.13039/100000025
                Award ID: R21MH102113-01A1
                Award Recipient : Joan W. Berman
                Funded by: HHS | NIH | National Institute of Mental Health (NIMH) https://doi.org/10.13039/100000025
                Award ID: R01MH090958
                Award Recipient : Joan W. Berman
                Categories
                Research Article
                Custom metadata
                September/October 2017

                Life sciences
                cns,hiv,cognition,qpcr,reservoirs
                Life sciences
                cns, hiv, cognition, qpcr, reservoirs

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