Impaired Lymphoid Chemokine-Mediated Migration due to a Block on the Chemokine Receptor Switch in Human Cytomegalovirus-Infected Dendritic Cells

Section of Infection and Immunity. Department of Medicine, University of Wales College of Medicine, Cardiff, United Kingdom.
Journal of Virology (Impact Factor: 4.44). 04/2004; 78(6):3046-54. DOI: 10.1128/JVI.78.6.3046-3054.2004
Source: PubMed


Dendritic cell (DC) migration from the site of infection to the site of T-cell priming is a crucial event in the generation
of antiviral T-cell responses. Here we present to our knowledge the first functional evidence that human cytomegalovirus (HCMV)
blocks the migration of infected monocyte-derived DCs toward lymphoid chemokines CCL19 and CCL21. DC migration is blocked
by viral impairment of the chemokine receptor switch at the level of the expression of CCR7 molecules. The inhibition occurs
with immediate-early-early kinetics, and viral interference with NF-κB signaling is likely to be at least partially responsible
for the lack of CCR7 expression. DCs which migrate from the infected cultures are HCMV antigen negative, and consequently
they do not stimulate HCMV-specific CD8+ T cells, while CD4+-T-cell activation is not impaired. Although CD8+ T cells can also be activated by alternative antigen presentation mechanisms, the spatial segregation of naive T cells and
infected DCs seems a potent mechanism of delaying the generation of primary CD8+-T-cell responses and aiding early viral spread.

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Available from: Zsuzsanna Tabi, Oct 09, 2015
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    • "What became clear from such data was that HCMV infection of DCs resulted in a severe down-regulation of cell surface molecules which impacted on the normal function of DCs as APCs (Riegler et al., 2000; Grigoleit et al., 2002; Moutaftsi et al., 2002, 2004; Hertel et al., 2003; Lee et al., 2006, 2011; Huang et al., 2012). Although viral genes encoding immune evasion functions are expressed in all cell types, the sheer abundance of immune-evasins expressed by the virus suggests the evolution of an intimate relationship between HCMV and key immune effector cells – e.g., the DC lineage. "
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    ABSTRACT: Primary infection of healthy individuals with human cytomegalovirus (HCMV) is normally asymptomatic but results in the establishment of a lifelong infection of the host. One important cellular reservoir of HCMV latency is the CD34+ haematopoietic progenitor cells resident in the bone marrow. Viral gene expression is highly restricted in these cells with an absence of viral progeny production. However, cellular differentiation into mature myeloid cells is concomitant with the induction of a full lytic transcription program, DNA replication and, ultimately, the production of infectious viral progeny. Such reactivation of HCMV is a major cause of morbidity and mortality in a number of immune-suppressed patient populations. Our current understanding of HCMV carriage and reactivation is that cellular differentiation of the CD34+ progenitor cells through the myeloid lineage, resulting in terminal differentiation to either a macrophage or dendritic cell (DC) phenotype, is crucial for the reactivation event. In this mini-review, we focus on the interaction of HCMV with DCs, with a particular emphasis on their role in reactivation, and discuss how the critical regulation of viral major immediate-early gene expression appears to be delicately entwined with the activation of cellular pathways in differentiating DCs. Furthermore, we also explore the possible immune consequences associated with reactivation in a professional antigen presenting cell and potential countermeasures HCMV employs to abrogate these.
    Frontiers in Microbiology 08/2014; 5:389. DOI:10.3389/fmicb.2014.00389 · 3.99 Impact Factor
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    • "A switch from CCR5 to CCR7 during DC maturation enables the cells respond to these chemokines. However, HCMV can prevent this chemokine receptor switch in infected moDCs—and thereby inhibit migration of mature moDCs in response to CCL19 and CCL21.70 In immature moDCs, HCMV infection impairs chemotaxis in response to CCL3 and CCL5, and internalizes CCR1 and CCR5, but does not affect CCR7.71 "
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    ABSTRACT: Human cytomegalovirus (HCMV), a member of the herpesvirus family, establishes life-long persistence and latency after primary infection and can be reactivated later in life. In immunosuppressed patients, it is an important pathogen that can cause severe disease. HCMV is also thought to play a causative role in inflammatory diseases and cancer. The virus can infect different immune cells, including dendritic cells (DCs) and can take advantage of host immune functions to avoid immune recognition. These characteristics have sparked major interest in understanding HCMV and its interaction with immune cells and their relevance to disease pathogenesis. In this review, we focus on the complex host-pathogen relationship between HCMV and DCs, including the persistence of the virus in these cells, their function in the immune response to HCMV infection and the potential clinical consequences of HCMV infection in DCs.
    Virulence 10/2012; 3(7). DOI:10.4161/viru.22239 · 4.22 Impact Factor
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    • "Further, HCMV-infected, immature Mo- DCs have fewer surface HLA class I and class II molecules and impaired migratory and immunostimulatory capacity [74] [81] [82]. The virus also inhibits Mo-DC maturation and impedes the migration of mature DCs in response to lymphoid stimuli and induction of T-cell proliferation [75] [82] [83]. Similarly, on infection with HCMV, activation markers are downregulated in mature Langerhans DCs, decreasing their ability to stimulate T-cell proliferation [84] [85]. "
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    ABSTRACT: The interaction between human cytomegalovirus (HCMV) and its host is a complex process that begins with viral attachment and entry into host cells, culminating in the development of a specific adaptive response that clears the acute infection but fails to eradicate HCMV. We review the viral and cellular partners that mediate early host responses to HCMV with regard to the interaction between structural components of virions (viral glycoproteins) and cellular receptors (attachment/entry receptors, toll-like receptors, and other nucleic acid sensors) or intrinsic factors (PML, hDaxx, Sp100, viperin, interferon inducible protein 16), the reactions of innate immune cells (antigen presenting cells and natural killer cells), the numerous mechanisms of viral immunoevasion, and the potential exploitation of events that are associated with early phases of virus-host interplay as a therapeutic strategy.
    Mediators of Inflammation 05/2012; 2012(7):607276. DOI:10.1155/2012/607276 · 3.24 Impact Factor
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