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ABSTRACT: Migration of both uninfected and infected monocytes into the brain during acute HIV infection likely initiates metabolic changes that can be observed with magnetic resonance spectroscopy (MRS). Herein, we measured changes in brain metabolism during the first year of HIV infection and examined the relationship of these metabolite levels to CD16+ monocyte populations measured in the blood. MRS was performed on nine HIV+ subjects identified during acute HIV infection and nine seronegative control subjects. HIV+ subjects were examined within 90 days of an indeterminate Western blot, then again 2 and 6 months later, during early infection. Blood samples were collected for plasma viral RNA and monocyte subset quantification. HIV+ subjects were identified with acute viral ailment and did not display severe cognitive deficits such as dementia or minor cognitive motor disorder. Changes in lipid membrane metabolism (choline levels) in the frontal cortex and white matter were observed during the initial year of HIV infection. Greater numbers of CD16+ monocytes were associated with lower N-acetylaspartate levels and higher choline levels in the brain. These results suggest that HIV infection induces metabolic changes in the brain early during infection and that these changes may be related to monocyte dynamics in the periphery.
Journal of NeuroVirology 06/2011; 17(3):220-9. · 2.31 Impact Factor
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ABSTRACT: Monocytes/macrophages are critical components of HIV and SIV encephalitic lesions. We used in vivo BrdU labeling and markers specific to stages of macrophage differentiation or inflammation to define macrophage heterogeneity and to better define the role of macrophage populations in lesion formation and productive infection. Lesions were heterogeneously composed of resident macrophages (CD68(+)HAM56(+)), perivascular macrophages (CD163(+) CD68(+)MAC387(-)), and recently infiltrated MAC387(+) CD68(-)CD163(-) monocytes/macrophages. At 24 and 48 hours after BrdU inoculation, 30% of MAC387(+) monocytes/macrophages were BrdU(+), consistent with their being recently infiltrated. In perivascular cuffs with low-level SIV replication, MAC387(+) monocytes/macrophages outnumbered CD68(+) macrophages. Conversely, lesions with numerous SIV-p28(+) macrophages and multinucleated giant cells had fewer MAC387(+) monocytes/macrophages. The MAC387(+) cells were not productively infected nor did they express detectable CCR2, unlike perivascular macrophages. Overall, we found that the proportion of MAC387(+) cells tends to be higher than the proportion of CD68(+) macrophages in the brain of animals with mild encephalitis; the ratio was reversed with more severe encephalitis. These results suggest that development of SIV and HIV encephalitis is an active and ongoing process that involves the recruitment and accumulation of: i) nonproductively infected MAC387(+) monocytes/macrophages that are present with inflammation (potentially M1-like macrophages), ii) CD163(+) perivascular macrophages (consistent with M2-like macrophages), and iii) CD68(+) or HAM56(+) resident macrophages. The latter two populations are cellular reservoirs for productive infection.
American Journal Of Pathology 05/2011; 178(5):2121-35. · 4.89 Impact Factor
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ABSTRACT: Infection by HIV is associated with the expansion of monocytes expressing CD16 antigens, but the significance of this in HIV pathogenesis is largely unknown. In rhesus macaques, at least three subpopulations of blood monocytes were identified based on their expression of CD14 and CD16: CD14(high)CD16(-), CD14(high)CD16(low), and CD14(low)CD16(high). The phenotypes and functions of these subpopulations, including CD16(+) monocytes, were investigated in normal, uninfected rhesus macaques and macaques that were infected with SIV or chimeric SHIV. To assess whether these different monocyte subpopulations expand or contract in AIDS pathogenesis, we conducted a cross-sectional study of 54 SIV- or SHIV-infected macaques and 48 uninfected controls. The absolute numbers of monocyte populations were examined in acutely infected animals, chronically infected animals with no detectable plasma virus RNA, chronically infected animals with detectable plasma virus RNA, and animals that died with AIDS. The absolute numbers of CD14(high)CD16(low) and CD14(low)CD16(high) monocytes were elevated significantly in acutely infected animals and chronically infected animals with detectable plasma virus RNA compared with uninfected controls. Moreover, a significant, positive correlation was evident between the number of CD14(high)CD16(low) or CD14(low)CD16(high) monocytes and plasma viral load in the infected cohort. These data show the dynamic changes of blood monocytes, most notably, CD14(high)CD16(low) monocytes during lentiviral infection, which are specific to disease stage.
Journal of leukocyte biology 10/2009; 87(4):557-67. · 4.99 Impact Factor
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Atsuhiko Hasegawa,
Huining Liu,
Binhua Ling,
Juan T Borda,
Xavier Alvarez,
Chie Sugimoto,
Heather Vinet-Oliphant, Woong-Ki Kim,
Kenneth C Williams,
Ruy M Ribeiro,
Andrew A Lackner,
Ronald S Veazey,
Marcelo J Kuroda
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ABSTRACT: It is widely accepted that destruction of CD4(+) T cells and viral load are the primary markers for immunodeficiency in HIV-1-infected humans and in simian immunodeficiency virus (SIV)-infected macaques. However, monocyte/macrophages are also important targets of HIV/SIV infection and a critical link between innate and adaptive immunity. We therefore examined whether changes in cells of the monocyte/macrophage lineage could be linked to the pathogenesis of AIDS in the rhesus macaque model. Here, we show that massive turnover of peripheral monocytes associated with death of tissue macrophages correlates with AIDS progression in macaques. More importantly, the level of monocyte turnover was not linked to the CD4(+) T-cell count and was a better predictive marker for AIDS progression than was viral load or lymphocyte activation. Our results show the importance of monocyte/macrophages in the pathogenesis of AIDS and suggest the dynamic changes of the monocyte/macrophages as a new marker for AIDS progression.
Blood 05/2009; 114(14):2917-25. · 9.90 Impact Factor
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ABSTRACT: We characterized inflammatory infiltrates in archival brain biopsy and autopsy samples from 26 HIV(+) and 20 HIV(-) patients with progressive multifocal leukoencephalopathy (PML). The predominant inflammatory cells were CD8(+) T lymphocytes. We defined CD8(+) T cell distribution with regard to JCV-infected glial cells, PML lesions and the extent of demyelination. In most samples from either HIV(+) and HIV(-) patients, we found positive correlations between the parenchymal CD8(+) T cells and JCV-infected glial cells and conversely, negative correlations between the perivascular CD8(+) T cells and JCV-infected glial cells in the surrounding brain. Most of these correlations remained significant after accounting for the degree of demyelination and location of the cells relative to lesions. Moreover, high numbers of CD8(+) T cells were found within and at the border of active PML lesions. These results suggest that CD8(+) T cells are primarily associated with JCV-infected glial cells in most PML cases and that an active ongoing recruitment of CD8(+) T cells and possibly viral antigen-specific retention could occur. These observations are discussed in the context of the recent evidence of PML in multiple sclerosis and Crohn's patients treated with natalizumab, underscoring the role of CD8(+) T lymphocytes in continued immunosurveillance of the CNS.
Journal of NeuroVirology 05/2006; 12(2):116-28. · 2.31 Impact Factor
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ABSTRACT: Perivascular macrophages are uniquely situated at the intersection between the nervous and immune systems. Although combined myeloid marker detection differentiates perivascular from resident brain macrophages (parenchymal microglia), no single marker distinguishes perivascular macrophages in humans and mice. Here, we present the macrophage scavenger receptor CD163 as a marker for perivascular macrophages in humans, monkeys, and mice. CD163 was primarily confined to perivascular macrophages and populations of meningeal and choroid plexus macrophages in normal brains and in brains of humans and monkeys with human immunodeficiency virus or simian immunodeficiency virus (SIV) encephalitis. Scattered microglia in SIV encephalitis lesions and multinucleated giant cells were also CD163 positive. Consistent with prior findings that perivascular macrophages are primary targets of human immunodeficiency virus and SIV, all SIV-infected cells in the brain were CD163 positive. Using fluorescent dyes that definitively and selectively label perivascular macrophages in vivo, we confirmed that dye-labeled simian perivascular macrophages were CD163 positive and able to repopulate the central nervous system within 24 hours. Flow cytometric studies demonstrated a subset of monocytes (CD163(+)CD14(+)CD16(+)) that were immunophenotypically similar to brain perivascular macrophages. These findings recognize CD163(+) blood monocytes/macrophages as a source of brain perivascular macrophages and underscore the utility of this molecule in studying the biology of perivascular macrophages and their precursors in humans, monkeys, and mice.
American Journal Of Pathology 04/2006; 168(3):822-34. · 4.89 Impact Factor
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Kenneth Williams,
Susan Westmoreland,
Jane Greco,
Eva Ratai,
Margaret Lentz, Woong-Ki Kim,
Robert A Fuller,
John P Kim,
Patrick Autissier,
Prahbat K Sehgal,
Raymond F Schinazi,
Norbert Bischofberger,
Michael Piatak,
Jeffrey D Lifson,
Eliezer Masliah,
R Gilberto González
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ABSTRACT: Difficulties in understanding the mechanisms of HIV neuropathogenesis include the inability to study dynamic processes of infection, cumulative effects of the virus, and contributing host immune responses. We used H magnetic resonance spectroscopy and studied monocyte activation and progression of CNS neuronal injury in a CD8 lymphocyte depletion model of neuroAIDS in SIV-infected rhesus macaque monkeys. We found early, consistent neuronal injury coincident with viremia and SIV infection/activation of monocyte subsets and sought to define the role of plasma virus and monocytes in contributing to CNS disease. Antiretroviral therapy with essentially non-CNS-penetrating agents resulted in slightly decreased levels of plasma virus, a significant reduction in the number of activated and infected monocytes, and rapid, near-complete reversal of neuronal injury. Robust macrophage accumulation and productive virus replication were found in brains of infected and CD8 lymphocyte-depleted animals, but no detectable virus and few scattered infiltrating macrophages were observed in CD8 lymphocyte-depleted animals compared with animals not receiving antiretroviruses that were sacrificed at the same time after infection. These results underscore the role of activated monocytes and monocyte infection outside of the brain in driving CNS disease.
Journal of Clinical Investigation 10/2005; 115(9):2534-45. · 15.39 Impact Factor
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ABSTRACT: Increased in vivo expression of intramuscularly delivered plasmid DNA will be essential for clinical success in gene therapy and plasmid DNA vaccination. We screened polymers from a library of beta-amino esters for their ability to augment transgene expression as measured by beta-galactosidase activity and cellular immune responses. Among the candidates identified in this screen, poly[(1,6-di(acryloxyethoxy)hexane)-co-(4-aminobutanol)] enhanced plasmid DNA transgene expression by sevenfold (P=0.0001) and its immunogenicity by 70% (P=0.03). We found that polymers with moderately hydrophobic backbones and terminal alcohol groups facilitated transfection most effectively in vivo. We also observed a log-linear correlation (R2=0.93) between peak cellular immune responses and transgene activity in all evaluated polymer-plasmid DNA formulations, clarifying the relationship between immunogenicity and the quantity of expressed antigen.
Molecular Therapy 08/2005; 12(1):164-70. · 6.87 Impact Factor
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ABSTRACT: Recent evidence supports the notion that the endocannabinoid system may play a crucial role in neuroinflammation. We explored the changes that some elements of this system exhibit in a macaque model of encephalitis induced by simian immunodeficiency virus. Our results show that profound alterations in the distribution of specific components of the endocannabinoid system occur as a consequence of the viral infection of the brain. Specifically, expression of cannabinoid receptors of the CB2 subtype was induced in the brains of infected animals, mainly in perivascular macrophages, microglial nodules, and T-lymphocytes, most likely of the CD8 subtype. In addition, the endogenous cannabinoid-degrading enzyme fatty acid amide hydrolase was overexpressed in perivascular astrocytes as well as in astrocytic processes reaching cellular infiltrates. Finally, the pattern of CB1 receptor expression was not modified in the brains of infected animals compared with that in control animals. These results resemble previous data obtained in Alzheimer's disease human tissue samples and suggest that the endocannabinoid system may participate in the development of human immunodeficiency virus-induced encephalitis, because activation of CB2 receptors expressed by immune cells is likely to reduce their antiviral response and thus could favor the CNS entry of infected monocytes.
Journal of Neuroscience 04/2005; 25(10):2530-6. · 7.11 Impact Factor
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Woong-Ki Kim,
Sarah Corey,
Gillian Chesney,
Heather Knight,
Sherry Klumpp,
Christian Wüthrich,
Norman Letvin,
Igor Koralnik,
Andrew Lackner,
Ronald Veasey,
Kenneth Williams
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ABSTRACT: T lymphocytes are found within brains infected with human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) where they are a minor, but consistently identified, population. However, little analysis of their phenotypes has been done, and questions concerning whether or not they are viral antigen specific has not been thoroughly examined. We investigated the central nervous system (CNS) of SIV-infected rhesus macaques to identify T-lymphocyte subsets in relation to virus-infected cells and brain microvessels. We have found that a sensitive antigen-retrieval technique greatly enhanced immunohistochemical detection of CD4+ and CD8+ T lymphocytes in control studies. In encephalitic brains of SIV-infected monkeys with acquired immunodeficiency syndrome (AIDS), we found a significant accumulation of CD8+ T lymphocytes but little-to-no accumulation of CD4+ T lymphocytes. CD4+ cells, when detected, were mostly monocyte/macrophages closely associated with CNS vessels. Using a combination of in situ hybridization for SIV RNA, and immunohistochemistry for CD8+ T lymphocytes and/or Glut-1 for endothelial cells on brain microvessels, we found CD8+ T lymphocytes with an angiocentric distribution often adjacent to virus-infected cells. In the CNS of animals with SIV encephalitis, there was a trend of CD8+ T lymphocytes that were not directly juxtaposed with CNS vessels. These data suggest that in brains of SIV-infected monkeys and HIV-infected humans, CD8+ T lymphocytes traffic to and are retained in the CNS in an angiocentric and possibly antigen-specific manner.
Journal of NeuroVirology 11/2004; 10(5):315-25. · 2.31 Impact Factor
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ABSTRACT: This short review focuses on the role of central nervous system (CNS) perivascular macrophages as targets of productive infection of the CNS. Data discussed include the importance of these cells as early targets of infection and their productive infection with AIDS. Many of the immune molecules on perivascular macrophages are also found on subsets of blood monocyte/macrophages, some of which are expanded during human immunodeficiency virus (HIV) infection. These observations paired with the known bone marrow (BM) origin of perivascular macrophages and the BM as a site of HIV infection underscore the importance of the study of monocyte populations in the BM and blood, which are activated and infected as a source of virus that enters the CNS. Data presented and discussed herein suggest a role of HIV-infected BM-derived monocytes as "Trojan horse" cells that traffic to the CNS to become perivascular macrophages. The study of such cells including their timing of infection, activation, and traffic and the role of HIV-specific immune responses controlling their accumulation in the CNS warrant study with regard to CNS neuropathogenesis.
Journal of Leukocyte Biology 12/2003; 74(5):650-6. · 4.99 Impact Factor
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Sallie R Permar,
Sherry A Klumpp,
Keith G Mansfield, Woong-Ki Kim,
Darci A Gorgone,
Michelle A Lifton,
Kenneth C Williams,
Jörn E Schmitz,
Keith A Reimann,
Michael K Axthelm,
Fernando P Polack,
Diane E Griffin,
Norman L Letvin
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ABSTRACT: The creation of an improved vaccine for global measles control will require an understanding of the immune mechanisms of measles virus containment. To assess the role of CD8(+) cytotoxic T lymphocytes in measles virus clearance, rhesus monkeys were depleted of CD8(+) lymphocytes by monoclonal anti-CD8 antibody infusion and challenged with wild-type measles virus. The CD8(+) lymphocyte-depleted animals exhibited a more extensive rash, higher viral loads at the peak of virus replication, and a longer duration of viremia than did the control antibody-treated animals. These findings indicate a central role for CD8(+) lymphocytes in the control of measles virus infections and the importance of eliciting a cell-mediated immune response in new measles vaccine strategies.
Journal of Virology 05/2003; 77(7):4396-400. · 5.40 Impact Factor
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ABSTRACT: Microglia are intrinsic mediators of the central nervous system (CNS) immune response induced by a variety of insults. Activated microglia express costimulatory molecules CD40 and B7 that are important equally for T-cell activation and further activation of microglia. In this study, we sought to investigate the regulation of costimulatory molecule expression on primary microglia and microglial cell line, BV-2, by pituitary adenylyl cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP), potent anti-inflammatory neuropeptides. The neuropeptides inhibited CD40 and B7-2 mRNA expression in activated microglia. PACAP decreased surface expression of CD40 and B7-2 on activated microglia. The inclusion of an anti-IL-10 antibody completely abrogated PACAP inhibition of lipopolysaccharide (LPS)-induced CD40 expression, suggesting that PACAP inhibition is at least in part mediated by IL-10. Indeed, PACAP enhanced LPS-induced IL-10 mRNA and protein levels in microglia. These data indicate that PACAP, through an increase in IL-10 protein, can down-regulate important costimulatory molecule expression on microglia, thereby possibly affecting CNS immunity.
Journal of Neuroimmunology 06/2002; 126(1-2):16-24. · 2.96 Impact Factor
