Human cytomegalovirus infection reduces surface CCR5 expression in human microglial cells, astrocytes and monocyte-derived macrophages

Lecointe, Didier; Dugas, Nathalie; Leclerc, Philippe; Héry, Christiane; Delfraissy, Jean‐François; Tardieu, Marc

doi:10.1016/s1286-4579(02)00022-9

Cited by 13 publications

(12 citation statements)

References 34 publications

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“…Results showed that CHME-5 microglia cells expressed the CD4 and CCR5 receptors with a mean fluorescence intensity (MFI) of 20 and 60 respectively (Supplementary Figure 1A–C). These results are similar to human primary fetal microglia cells (Lecointe et al 2002). After HIV-1 infection, CHME-5 microglia showed an increase in p24 antigen levels after 3 dpi (p<0.05), reaching 500 pg/mL at 12 dpi (Supplementary Figure 1D).…”

Section: Resultssupporting

confidence: 86%

HIV-infected microglia mediate cathepsin B-induced neurotoxicity

et al. 2015

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BACKGROUND HIV-1-infected mononuclear phagocytes release soluble factors that affect the homeostasis in tissue. HIV-1 can prompt metabolic encephalopathy with the addition of neuronal dysfunction and apoptosis. Recently, we reported that HIV-1 enhances the expression and secretion of bioactive cathepsin B in monocyte-derived macrophages, ultimately contributing to neuronal apoptosis. In this research, we request if microglia respond to HIV infection similarly by modifying the expression, secretion, neurotoxic potential of cathepsin B and the in vivo relevance of these findings. METHODS HIV-ADA infected human primary microglia and CHME-5 were assessed for expression and activity of cathepsin B, its inhibitors, cystatins B and C, and neurotoxicity associated with these changes. Human primary neurons were exposed to supernatants from HIV-infected and uninfected microglia in the presence of cathepsin B inhibitors and apoptosis was assessed by TUNEL. Microglial expression of cathepsin B was validated in brain tissue from HIVE patients. RESULTS HIV-infected microglia secreted significantly greater levels of cathepsin B, cystatin B, and cystatin C compared to uninfected cells. Increased apoptosis was observed in neurons exposed to supernatants from HIV-1 infected microglia at days 12 post-infection. The cathepsin B inhibitor CA-074 and cathepsin B antibody prevented neuronal apoptosis. Increased microglia-derived cathepsin B, cystatin B, and cystatin C and caspase-3+ neurons were detected in HIVE brains compared to controls. CONCLUSIONS Our results suggest that HIV-1-induced cathepsin B production in microglia contributes to neuronal apoptosis and may be an important factor in neuronal death associated with HIVE.

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Section: Resultssupporting

confidence: 86%

HIV-infected microglia mediate cathepsin B-induced neurotoxicity

et al. 2015

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“…From these earlier evaluations, HCMV infection does not appear to contribute significantly to HAD (294,366). However, the HIV entry coreceptor CCR5 is suppressed in astrocytes, microglia, and monocyte-derived macrophages infected with HCMV (189). In monocyte-derived macrophages this process impaired HIV infection, although in astrocytes and microglia this was not apparent.…”

Section: Virusesmentioning

confidence: 89%

Role of Microglia in Central Nervous System Infections

et al. 2004

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The nature of microglia fascinated many prominent researchers in the 19th and early 20th centuries, and in a classic treatise in 1932, Pio del Rio-Hortega formulated a number of concepts regarding the function of these resident macrophages of the brain parenchyma that remain relevant to this day. However, a renaissance of interest in microglia occurred toward the end of the 20th century, fueled by the recognition of their role in neuropathogenesis of infectious agents, such as human immunodeficiency virus type 1, and by what appears to be their participation in other neurodegenerative and neuroinflammatory disorders. During the same period, insights into the physiological and pathological properties of microglia were gained from in vivo and in vitro studies of neurotropic viruses, bacteria, fungi, parasites, and prions, which are reviewed in this article. New concepts that have emerged from these studies include the importance of cytokines and chemokines produced by activated microglia in neurodegenerative and neuroprotective processes and the elegant but astonishingly complex interactions between microglia, astrocytes, lymphocytes, and neurons that underlie these processes. It is proposed that an enhanced understanding of microglia will yield improved therapies of central nervous system infections, since such therapies are, by and large, sorely needed

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“…Previous reports demonstrated that infection of different cell types with HCMV has diverse effects on CXCR4. Lecointe et al showed that HCMV infection of microglial cells, but not of macrophages or astrocytes, leads to the downregulation of CXCR4 (62). Moreover, CXCL12-mediated migration of HCMV-infected cytotrophoblasts was found to be impaired, although CXCR4 surface expression was induced (63).…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus-Induced Degradation of CYTIP Modulates Dendritic Cell Adhesion and Migration

et al. 2017

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As potent antigen-presenting cells, dendritic cells (DCs) are essential for the initiation of effective antiviral immune responses. Viruses and especially herpesviruses, which are able to establish lifelong persistence, exploit several immune evasion mechanisms targeting DC biology. Our group has previously shown that the α-herpesvirus herpes simplex virus type 1 inhibits mature DC (mDC) migration by inducing adhesion via degrading the cellular protein CYTIP (cytohesin-1 interacting protein), an important negative regulator of β2-integrin activity. In the present study, we extended our analysis to the β-herpesvirus human cytomegalovirus (HCMV), to investigate whether other herpesviridae also induce such modulations. Indeed, HCMV impairs mDC transwell migration capability following a CCL19-chemokine gradient, despite equivalent expression levels of the cognate chemokine receptor CCR7 at the corresponding time points post-infection. Remarkably, HCMV infection potently induced β2-integrin activity on mDCs. Furthermore, directly HCMV-infected mDCs, exhibiting viral gene expression, strongly adhere to fibronectin and ICAM-1, in contrast to mDCs lacking infection or viral gene expression. Interestingly, HCMV-positive mDCs display a proteasome-dependent degradation of CYTIP. Contrasting the migration toward CCL19, elevated expression levels of the chemokine receptor CXCR4 in HCMV-infected mDCs were associated with functional CXCL12-chemotaxis under the herein used conditions. In summary, our results show that HCMV shapes mDC adhesion to compromise migration toward CCL19, but retaining CXCL12 responsiveness. Thus, we hypothesize that a preferred migration pattern toward the bone marrow, but not to secondary lymphoid organs, could ultimately cause a failure in the induction of potent antiviral immune responses.

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Human cytomegalovirus infection reduces surface CCR5 expression in human microglial cells, astrocytes and monocyte-derived macrophages

Cited by 13 publications

References 34 publications

HIV-infected microglia mediate cathepsin B-induced neurotoxicity

HIV-infected microglia mediate cathepsin B-induced neurotoxicity

Role of Microglia in Central Nervous System Infections

Human Cytomegalovirus-Induced Degradation of CYTIP Modulates Dendritic Cell Adhesion and Migration

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