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      Increased Monocyte Turnover from Bone Marrow Correlates with Severity of SIV Encephalitis and CD163 Levels in Plasma

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          Abstract

          Cells of the myeloid lineage are significant targets for human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in monkeys. Monocytes play critical roles in innate and adaptive immunity during inflammation. We hypothesize that specific subsets of monocytes expand with AIDS and drive central nervous system (CNS) disease. Additionally, there may be expansion of cells from the bone marrow through blood with subsequent macrophage accumulation in tissues driving pathogenesis. To identify monocytes that recently emigrated from bone marrow, we used 5-bromo-2′-deoxyuridine (BrdU) labeling in a longitudinal study of SIV-infected CD8+ T lymphocyte depleted macaques. Monocyte expansion and kinetics in blood was assessed and newly migrated monocyte/macrophages were identified within the CNS. Five animals developed rapid AIDS with differing severity of SIVE. The percentages of BrdU+ monocytes in these animals increased dramatically, early after infection, peaking at necropsy where the percentage of BrdU+ monocytes correlated with the severity of SIVE. Early analysis revealed changes in the percentages of BrdU+ monocytes between slow and rapid progressors as early as 8 days and consistently by 27 days post infection. Soluble CD163 (sCD163) in plasma correlated with the percentage of BrdU+ monocytes in blood, demonstrating a relationship between monocyte activation and expansion with disease. BrdU+ monocytes/macrophages were found within perivascular spaces and SIVE lesions. The majority (80–90%) of the BrdU+ cells were Mac387+ that were not productively infected. There was a minor population of CD68+BrdU+ cells (<10%), very few of which were infected (<1% of total BrdU+ cells). Our results suggest that an increased rate of monocyte recruitment from bone marrow into the blood correlates with rapid progression to AIDS, and the magnitude of BrdU+ monocytes correlates with the severity of SIVE.

          Author Summary

          Human immunodeficiency virus (HIV) and the closely related simian immunodeficiency virus (SIV) can infect monocyte/macrophages, which enter and accumulate in the brain leading to neuronal dysfunction. Monocyte/macrophages exit the bone marrow, transit through the blood and enter the central nervous system (CNS). What triggers these cells to traffic is undefined, but it occurs in normal non-infected conditions at a rate that is accelerated with viral infection. Here, we used 5-bromo-2′-deoxyuridine (BrdU) injection and incorporation into the DNA of monocytes prior to their departure from the bone marrow. We found that the percentage of BrdU+ monocytes leaving the bone marrow 24 hours after injection increased in animals that rapidly succumbed to AIDS and correlated with the severity of SIV encephalitis (SIVE). Differences in BrdU labeled monocytes in slow and rapid progressors were revealed as early as 8 days and were consistent by 27 days post infection. Soluble CD163, shed by activated monocyte/macrophages, directly correlated with BrdU+ monocyte expansion. Our study provides new insights into the development of HIV-related CNS disease and underscores the importance of monocyte/macrophage recruitment from the bone marrow as an AIDS defining event.

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          Most cited references57

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          Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes.

          Clinical evidence suggests that cellular immunity is involved in controlling human immunodeficiency virus-1 (HIV-1) replication. An animal model of acquired immune deficiency syndrome (AIDS), the simian immunodeficiency virus (SIV)-infected rhesus monkey, was used to show that virus replication is not controlled in monkeys depleted of CD8+ lymphocytes during primary SIV infection. Eliminating CD8+ lymphocytes from monkeys during chronic SIV infection resulted in a rapid and marked increase in viremia that was again suppressed coincident with the reappearance of SIV-specific CD8+ T cells. These results confirm the importance of cell-mediated immunity in controlling HIV-1 infection and support the exploration of vaccination approaches for preventing infection that will elicit these immune responses.
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            Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4.

            Stem cell homing and repopulation are not well understood. The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 were found to be critical for murine bone marrow engraftment by human severe combined immunodeficient (SCID) repopulating stem cells. Treatment of human cells with antibodies to CXCR4 prevented engraftment. In vitro CXCR4-dependent migration to SDF-1 of CD34+CD38-/low cells correlated with in vivo engraftment and stem cell function. Stem cell factor and interleukin-6 induced CXCR4 expression on CD34+ cells, which potentiated migration to SDF-1 and engraftment in primary and secondary transplanted mice. Thus, up-regulation of CXCR4 expression may be useful for improving engraftment of repopulating stem cells in clinical transplantation.
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              Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli.

              CD163, also referred to as M130, a member of the scavenger receptor cysteine-rich family (SRCR) is exclusively expressed on cells of the monocyte lineage. In freshly isolated monocytes the CD14bright CD16+ monocyte subset revealed the highest expression of CD163 among all monocyte subsets. CD163 mRNA and protein expression is up-regulated during macrophage colony-stimulating factor (M-CSF)-dependent phagocytic differentiation of human blood monocytes. In contrast, monocytic cells treated with GM-CSF and interleukin-4 (IL-4) for dendritic differentiation down-regulate this antigen. CD163 expression is also suppressed by proinflammatory mediators like lipopolysaccharide (LPS), interferon-gamma (IFN-gamma), and tumor necrosis factor alpha, whereas IL-6 and the antiinflammatory cytokine interleukin-10 (IL-10) strongly up-regulate CD163 mRNA in monocytes and macrophages. The effects of the immunosuppressants dexamethasone, cyclosporin A (CA), and cortisol differ in their capacity to influence CD163 mRNA levels. Our results demonstrate that CD163 expression in monocytes/macrophages is regulated by proinflammatory and antiinflammatory mediators. This expression pattern implies a functional role of CD 163 in the antiinflammatory response of monocytes.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                April 2010
                April 2010
                15 April 2010
                : 6
                : 4
                : e1000842
                Affiliations
                [1 ]Biology Department, Boston College, Chestnut Hill, Massachusetts, United States of America
                [2 ]Division of Immunology, Tulane National Primate Research Center, Tulane University Health Science Center, Covington, Louisiana, United States of America
                [3 ]Division of Comparative Pathology, Tulane National Primate Research Center, Tulane University Health Science Center, Covington, Louisiana, United States of America
                NIH/NIAID, United States of America
                Author notes

                Conceived and designed the experiments: T. Burdo, K. Williams. Performed the experiments: T. Burdo, K. Orzechowski, J. Button, A. Krishnan, X. Alvarez. Analyzed the data: T. Burdo, C. Soulas, X. Alvarez, K. Williams. Contributed reagents/materials/analysis tools: K. Williams. Wrote the paper: T. Burdo, K. Williams. Intellectual input: C. Soulas, C. Sugimoto, M. Kuroda.

                Article
                09-PLPA-RA-1515R3
                10.1371/journal.ppat.1000842
                2855320
                20419144
                adda91e7-2916-47d1-a095-9bbb290e88c9
                Burdo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 1 September 2009
                : 3 March 2010
                Page count
                Pages: 13
                Categories
                Research Article
                Hematology/Hematopoiesis
                Immunology/Immunity to Infections
                Immunology/Leukocyte Activation
                Infectious Diseases/HIV Infection and AIDS
                Infectious Diseases/Viral Infections
                Pathology/Immunology
                Virology/Animal Models of Infection
                Virology/Immune Evasion
                Virology/Immunodeficiency Viruses

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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