Fischer-Smith T, Bell C, Croul S, et al. Monocyte/macrophage trafficking in acquired immunodeficiency syndrome encephalitis: lessons from human and nonhuman primate studies

Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania 19122, USA.
Journal of NeuroVirology (Impact Factor: 2.6). 09/2008; 14(4):318-26. DOI: 10.1080/13550280802132857
Source: PubMed


Here the authors discuss evidence in human and animal models supporting two opposing views regarding the pathogenesis of human immunodeficiency virus (HIV) in the central nervous system (CNS): (1) HIV infection in the CNS is a compartmentalized infection, with the virus-infected macrophages entering the CNS early, infecting resident microglia and astrocytes, and achieving a state of latency with evolution toward a fulminant CNS infection late in the course of disease; or alternatively, (2) events in the periphery lead to altered monocyte/macrophage (MPhi) homeostasis, with increased CNS invasion of infected and/or uninfected MPhis. Here the authors have reevaluated evidence presented in the favor of the latter model, with a discussion of phenotypic characteristics distinguishing normal resident microglia with those accumulating in HIV encephalitis (HIVE). CD163 is normally expressed by perivascular MPhi s but not resident microglia in normal CNS of humans and rhesus macaques. In agreement with other studies, the authors demonstrate expression of CD163 by brain MPhi s in HIVE and simian immunodeficiency virus encephalitis (SIVE). CNS tissues from HIV-sero positive individuals with HIVE or HIV-associated progressive multifocal leukoencephalopathy (PML) were also examined. In HIVE, the authors further demonstrate colocalization of CD163 and CD16 (Fcgamma III recptor) gene expression, the latter marker associated with HIV infection of monocyte in vivo and permissivity of infection. Indeed, CD163(+) MPhis and microglia are often productively infected in HIVE CNS. In SIV infected rhesus macaques, CD163(+) cells accumulate perivascularly, within nodular lesions and the parenchyma in animals with encephalitis. Likewise, parenchymal microglia and perivascular MPhi s are CD163(+) in HIVE. In contrast to HIVE, CD163(+)perivascular and parenchymal MPhi s in HIV-associated PML were only associated with areas of demyelinating lesions. Interestingly, SIV-infected rhesus macaques whose viral burden was predominantly at 1 x 10(6) copies/ml or greater developed encephalitis. To further investigate the relationship between CD163(+)/CD16(+) MPhis/microglia in the CNS and altered homeostasis in the periphery, the authors performed flow-cytometric analyses of peripheral blood mononuclear cells (PBMCs) from SIV-infected rhesus macaques. The results demonstrate an increase in the percent frequency of CD163(+)/CD16(+) monocytes in animals with detectable virus that correlated significantly with increased viral burden and CD4(+) T-cell decline. These results suggest the importance of this monocyte subset in HIV/SIV CNS disease, and also in the immune pathogenesis of lentiviral infection. The authors further discuss the potential role of CD163(+)/CD16(+) monocyte/MPhi subset expansion, altered myeloid homeostasis, and potential consequences for immune polarization and suppression. The results and discussion here suggest new avenues for the development of acquired immunodeficiency syndrome (AIDS) therapeutics and vaccine design.

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Available from: Tracy Fischer, Jul 23, 2014
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    • "A more profound relationship with HIV disease progression is suggested; however, when the CD16 + monocyte subset is further subfractionated by CD163 expression, where a positive correlation with CD16 + /CD163 + monocyte frequency and viral load, as well as CD4 + T cell loss in individuals with 450 cells/í µí¼‡L or less, has been observed [216]. Interestingly, these cells are phenotypically similar to MΦs that accumulate in HIVE brain, comprise perivascular cuffs and nodular lesions, and serve as the principal reservoir of productive virus in brain [218, 219]. Further, this increase in total brain MΦs in HIVE appears to be due to trafficking of monocytes/MΦs from the periphery, rather than microglial proliferation [220]. "
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    • "The presence of activated monocytes has also been associated with neurocognitive impairment but we did not see this in our study. CD163 is a scavenger receptor expressed on monocytes and macrophages that are thought to be precursors of perivascular macrophages that traffic to the brain [6,12]. They are seen in higher frequencies in HIV-infected subjects compared to healthy controls, and increased frequencies are associated with HIV viremia and low CD4 count [12]. "
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    • "Additionally, the relationship between in vitro observations and in vivo dynamics is not fully elucidated. Much evidence exists to support the existence of HIV-1 replication in macrophage/ macrophage-like cells in vivo [5] [6] [7] [8] [9] [10] [11], including a recent report from Deleage et al., and confirmed the presence of HIV-1 in macrophages within seminal vesicles of patients on effective highly active antiretroviral therapy (HAART) [12]. Correspondingly, a variety of studies have presented evidence that monocytes harbor productive viral replication in patients receiving HAART [13] [14], with other reports demonstrating that CD16 + monocytes, a subset of monocytes , are a source of HIV-1 permissive cells that preferentially harbor HIV-1 in vivo [15]. "
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