Measles virus‐induced suppression of immune responses

Griffin, Diane E.

doi:10.1111/j.1600-065x.2010.00925.x

Cited by 160 publications

(150 citation statements)

References 204 publications

(306 reference statements)

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“…The propensity of HCV to infect the immune system is consistent with a significantly greater prevalence of lymphoproliferative disorders, such as non-Hodgkin's lymphoma and mixed cryoglobulinemia, and perhaps mucosa-associated lymphoid tissue lymphoma, in patients infected with HCV (4,10,13,40,42). It also is possible that HCV residing in immune cells, like other persistent viral infections (5,14,26,29), is an important contributor to longterm virus persistence and that the infected immune cells are reservoirs from which infection can spread, for example, in patients grafted with new livers due to HCV-related end-stage disease or in recipients of seemingly HCV-negative donor organs (24,25,39).…”

mentioning

confidence: 89%

Hepatitis C Virus Infection of Human T Lymphocytes Is Mediated by CD5

Sarhan

Pham

Chen

et al. 2012

J Virol

109

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Hepatitis C virus (HCV) is one of the main causes of chronic liver disease. Although infection of hepatocytes is mainly responsible for manifestations of hepatitis C, the virus also invades the immune system by a yet-to-be-identified mechanism. Using human T cell lines and primary T lymphocytes as targets and patient-derived HCV as inocula, we aimed to identify how HCV gains entry into these cells. HCV replication was determined by detection of the HCV RNA replicative (negative) strand and viral proteins, while specific antibodies, knocking down gene expression and making otherwise-resistant cells prone to HCV, were employed to identify a receptor molecule determining T lymphocyte permissiveness to HCV infection. The results revealed that T cell susceptibility to HCV requires CD5, a lymphocyte-specific glycoprotein belonging to the scavenger receptor cysteine-rich family. Blocking of T cell CD5 with antibody or silencing with specific short hairpin RNA (shRNA) decreased cell susceptibility to HCV, while increasing CD5 expression by mitogen stimulation had the opposite effect. Moreover, transfection of naturally CD5-deficient HEK-293 fibroblasts with CD5 facilitated infection of these otherwise HCV-resistant cells. In contrast to T cells, hepatocytes do not express CD5. The data revealed that CD5 is a molecule important for HCV entry into human T lymphocytes. This finding provides direct insight into the mechanism of HCV lymphotropism and defines a target for potential interventions against HCV propagating in this extrahepatic compartment.

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mentioning

confidence: 89%

Hepatitis C Virus Infection of Human T Lymphocytes Is Mediated by CD5

Sarhan

Pham

Chen

et al. 2012

J Virol

109

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“…Clinical disease associated with infection by several paramyxoviruses such as mumps virus or measles virus (MeV) originate predominantly from immunopathogenic effects, which makes therapeutic treatment challenging, because viral replication is typically immune-controlled and titers decline when symptoms become manifest (14,15). In the case of RSV infection, however, several studies have suggested that pathogenesis is not the result of host immunopathology alone.…”

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confidence: 99%

Cross-resistance mechanism of respiratory syncytial virus against structurally diverse entry inhibitors

Yan

Lee

Thakkar

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

109

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Respiratory syncytial virus (RSV) is a leading pediatric pathogen that is responsible for a majority of infant hospitalizations due to viral disease. Despite its clinical importance, no vaccine prophylaxis against RSV disease or effective antiviral therapeutic is available. In this study, we established a robust high-throughput drug screening protocol by using a recombinant RSV reporter virus to expand the pool of RSV inhibitor candidates. Mechanistic characterization revealed that a potent newly identified inhibitor class blocks viral entry through specific targeting of the RSV fusion (F) protein. Resistance against this class was induced and revealed overlapping hotspots with diverse, previously identified RSV entry blockers at different stages of preclinical and clinical development. A structural and biochemical assessment of the mechanism of unique, broad RSV cross-resistance against structurally distinct entry inhibitors demonstrated that individual escape hotspots are located in immediate physical proximity in the metastable conformation of RSV F and that the resistance mutations lower the barrier for prefusion F triggering, resulting in an accelerated RSV entry kinetics. One resistant RSV recombinant remained fully pathogenic in a mouse model of RSV infection. By identifying molecular determinants governing the RSV entry machinery, this study spotlights a molecular mechanism of broad RSV resistance against entry inhibition that may affect the impact of diverse viral entry inhibitors presently considered for clinical use and outlines a proactive design for future RSV drug discovery campaigns.antiviral drugs | drug resistance

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“…MV infects primarily hematopoietic and epithelial cells and causes a severe transient immune suppression facilitating secondary infections that is due to interference with both innate and adaptive immune responses, including the type I IFN network (20,23,38,39,61).…”

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confidence: 99%

Measles Virus C Protein Interferes with Beta Interferon Transcription in the Nucleus

Sparrer

Pfaller

Conzelmann

2012

J Virol

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Transcriptional induction of beta interferon (IFN-␤) through pattern recognition receptors is a key event in the host defense against invading viruses. Infection of cells by paramyxoviruses, like measles virus (MV) (genus Morbillivirus), is sensed predominantly by the ubiquitous cytoplasmic helicase RIG-I, recognizing viral 5=-triphosphate RNAs, and to some degree by MDA5. While MDA5 activation is effectively prevented by the MV V protein, the viral mechanisms for inhibition of MDA5-independent induction of IFN-␤ remained obscure. Here, we identify the 186-amino-acid MV C protein, which shuttles between the nucleus and the cytoplasm, as a major viral inhibitor of IFN-␤ transcription in human cells. Activation of the transcription factor IRF3 by upstream kinases and nuclear import of activated IRF3 were not affected in the presence of C protein, suggesting a nuclear target. Notably, C proteins of wild-type MV isolates, which are poor IFN-␤ inducers, were found to comprise a canonical nuclear localization signal (NLS), whereas the NLSs of all vaccine strains, irrespective of their origins, were mutated. Site-directed mutagenesis of the C proteins from an MV wild-type isolate and from the vaccine virus strain Schwarz confirmed a correlation of nuclear localization and inhibition of IFN-␤ transcription. A functional NLS and efficient nuclear accumulation are therefore critical for MV C to retain its potential to downregulate IFN-␤ induction. We suggest that a defect in efficient nuclear import of C protein contributes to attenuation of MV vaccine strains.A ntiviral host defense relies on rapid recognition of invading viruses by pattern recognition receptors (PRRs), like the ubiquitous cytoplasmic RIG-I-like receptors (RLR), which include RIG-I, MDA5, and LGP-2, and a number of Toll-like receptors (TLR) operating mainly in specialized immune cells. Virus sensing by these receptors leads to activation of the transcription factors interferon regulatory factor 3 (IRF3) and IRF7 and nuclear factor kappa B (NF-B), which orchestrate transcriptional activation of type I interferons (alpha interferon [IFN-␣], IFN-␤, IFN-, and IFN-) and of proinflammatory cytokines (30, 43). Secreted early IFN-␤ alerts noninfected cells via binding to the IFN-␣ receptor (IFNAR) and activation of JAK/STAT signaling (50), which results in the induction of numerous IFN-stimulated genes (ISG). The established antiviral state limits further spread of the virus. As illustrated in the past decade, most viruses utilize multiple mechanisms to limit both the induction of and the response to type I IFN in order to be able to establish an infection (19,55,67). In the subfamily Paramyxovirinae, these functions are taken over by the diverse products of the phosphoprotein (P) gene (for a comprehensive review, see reference 22).Measles virus (MV) is a member of the genus Morbillivirus within the subfamily Paramyxovirinae and, in spite of the availability of safe live attenuated vaccines, remains a major cause of childhood mortality in developing countries (6...

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Measles virus‐induced suppression of immune responses

Cited by 160 publications

References 204 publications

Hepatitis C Virus Infection of Human T Lymphocytes Is Mediated by CD5

Hepatitis C Virus Infection of Human T Lymphocytes Is Mediated by CD5

Cross-resistance mechanism of respiratory syncytial virus against structurally diverse entry inhibitors

Measles Virus C Protein Interferes with Beta Interferon Transcription in the Nucleus

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