Epstein-Barr virus evasion of CD8+ and CD4+ T cell immunity via concerted actions of multiple gene products

Ressing, Maaike E.; Horst, Daniëlle; Griffin, Bryan D.; Tellam, Judy; Zuo, Jianmin; Khanna, Rajiv; Rowe, Martin; Wiertz, Emmanuel J. H. J.

doi:10.1016/j.semcancer.2008.10.008

Cited by 113 publications

(105 citation statements)

References 138 publications

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“…These observations were also consistent with MFold predictions of the codonmodified GAr mRNA folding into double-stranded structures, whereas the native EBNA1 GAr mRNA lacked a similar stem-loop structure ( Supplementary Fig. 6b) 6 . Notably, the bulges predicted for the native GAr mRNA by MFold analysis, which does not take into account G-quadruplex structure, encompass G-rich sequences such as g4-EBNA1, i.e., Gquadruplex motifs.…”

Section: Ebna1 Mrna Sequence Contains G-quadruplex Clusterssupporting

confidence: 86%

“…As G-quadruplex formation is dependent on the presence of potassium and parallel G-quadruplexes are characterized by a maximum at 266 nm 27 , these results demonstrated that G-quadruplexes form within EBNA1 mRNA. In contrast, a corresponding codon-modified EBNA1 GAr transcript (referred to as GArM), designed to reduce purine bias while maintaining the encoded native protein sequence 6 and in so doing initiate stem-loop structure, did not show a similar potassium dependency ( Supplementary Fig. 5), and its CD spectrum was characterized by a minimum at 210 nm ( Fig.…”

Section: Ebna1 Mrna Sequence Contains G-quadruplex Clustersmentioning

confidence: 99%

“…An overrepresentation of purine codons within the coding sequence of the Epstein-Barr virus maintenance protein, EBNA1 (ref. 5), correlates with an inhibition of mRNA translation and restricted endogenous presentation of CD8 + T-cell epitopes 6 . This purine bias is specifically observed within the region encoding the EBNA1 internal glycine-alanine repeat domain (GAr), which is critical for regulating EBNA1 self-synthesis and thereby for minimizing immune recognition [7][8][9][10][11][12][13][14][15][16][17][18][19][20] .…”

mentioning

confidence: 99%

“…This purine bias is specifically observed within the region encoding the EBNA1 internal glycine-alanine repeat domain (GAr), which is critical for regulating EBNA1 self-synthesis and thereby for minimizing immune recognition [7][8][9][10][11][12][13][14][15][16][17][18][19][20] . Reduction of purine codons within the EBNA1 GAr domain through codon modification markedly reverses this inhibitory effect 6 . Moreover, diverse EBNA1 GAr peptide sequences resulting from alternative reading frames do not alleviate the inhibitory effect on both EBNA1 selfsynthesis and the presentation of EBNA1 epitopes 17 and suggest that regulatory structural elements within the EBNA1 GAr encoding mRNA itself might regulate mRNA translation and antigen presentation.…”

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confidence: 99%

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G-quadruplexes regulate Epstein-Barr virus–encoded nuclear antigen 1 mRNA translation

et al. 2014

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Viruses that establish latent infections have evolved unique mechanisms to avoid host immune recognition. Maintenance proteins of these viruses regulate their synthesis to levels sufficient for maintaining persistent infection but below threshold levels for host immune detection. The mechanisms governing this finely tuned regulation of viral latency are unknown. Here we show that mRNAs encoding gammaherpesviral maintenance proteins contain within their open reading frames clusters of unusual structural elements, G-quadruplexes, which are responsible for the cisacting regulation of viral mRNA translation. By studying the Epstein-Barr virus-encoded nuclear antigen 1 (EBNA1) mRNA, we demonstrate that destabilization of G-quadruplexes using antisense oligonucleotides increases EBNA1 mRNA translation. In contrast, pretreatment with a G-quadruplex-stabilizing small molecule, pyridostatin, decreases EBNA1 synthesis, highlighting the importance of G-quadruplexes within virally encoded transcripts as unique regulatory signals

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Section: Ebna1 Mrna Sequence Contains G-quadruplex Clusterssupporting

confidence: 86%

Section: Ebna1 Mrna Sequence Contains G-quadruplex Clustersmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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G-quadruplexes regulate Epstein-Barr virus–encoded nuclear antigen 1 mRNA translation

et al. 2014

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“…22,25 Best known among pathogens that tamper major histocompatibility complex class I expression are herpesviruses, which can alter T-and natural killer-lymphocyte function by subverting the expression of host major histocompatibility complex molecules, or by encoding viral homologues of these. [26][27][28][29][30][31] As all of the polymorphisms of the LRC in chromosome 19, natural killer cells, herpesviruses and HLA class I molecules have been implicated in the susceptibility or pathogenesis of MS, 8,[32][33][34][35][36][37][38][39] it is also of interest to determine whether the genotypic diversity of KIR is associated with MS and whether such an association could explain, by linkage disequilibrium (LD), the reported relationship between MS and deletion of LILRA3.…”

Section: Introductionmentioning

confidence: 99%

Multiple sclerosis associates with LILRA3 deletion in Spanish patients

et al. 2009

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The genetic susceptibility to multiple sclerosis (MS) is only partially explained, and it shows geographic variations. We analyse here two series of Spanish patients and healthy controls and show that relapsing MS (R-MS) is associated with a gene deletion affecting the hypothetically soluble leukocyte immunoglobulin (Ig)-like receptor A3 (LILRA3, 19q13.4), in agreement with an earlier finding in German patients. Our study points to a gene-dose-dependent, protective role for LILRA3, the deletion of which synergizes with HLA-DRB1*1501 to increase the risk of R-MS. We also investigated whether the risk of suffering R-MS might be influenced by the genotypic diversity of killer-cell Ig-like receptors (KIRs), located only B400 kb telomeric to LILRA3, and implicated in autoimmunity and defence against viruses. The relationship of LILRA3 deletion with R-MS is not secondary to linkage disequilibrium with a KIR gene, but we cannot exclude some contributions of KIR to the genetic susceptibility to R-MS.

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Identification of novel CD8+ T cell epitopes in human herpesvirus 6B U11 and U90

Halawi

Khan

Blake

2015

Immunity Inflam & Disease

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Human herpesvirus 6B (HHV6B) infects over 90% of the population, and normally establishes a latent infection, where episodes of reactivation are asymptomatic. However, in immunocompromised patients HHV6B reactivation is associated with high morbidity and mortality. Cellular immunotherapy has been utilised against other herpesvirus in immunocompromised settings. However, limited information on the immune response against HHV6B has hampered the development of immunotherapy for HHV6B-driven disease. In this study, we have analysed the cellular immune response against four HHV6B antigens in a panel of 30 healthy donors. We show that the base-line level of T cell reactivity in peripheral blood is very low to undetectable. A short-term reactivation step enabled expansion of T cell responses, and all donors responded to at least 1 antigen, but more commonly 3 or 4. A hierarchy of immunogenicity was determined with antigens U90 and U54 being co-dominant, followed by U11 and U39. Putative CD8+ T cell epitopes were mapped to U90 and U11, predicted to be presented in the context of HLA-A1, A29, B39 and C6. T cells reactive against these novel epitopes were able to recognise virus-infected cells. Our data is supportive of the application and on-going development of T cell immunotherapy against HHVB-driven disease in the immunocompromised host.

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Epstein-Barr virus evasion of CD8+ and CD4+ T cell immunity via concerted actions of multiple gene products

Cited by 113 publications

References 138 publications

G-quadruplexes regulate Epstein-Barr virus–encoded nuclear antigen 1 mRNA translation

G-quadruplexes regulate Epstein-Barr virus–encoded nuclear antigen 1 mRNA translation

Multiple sclerosis associates with LILRA3 deletion in Spanish patients

Identification of novel CD8+ T cell epitopes in human herpesvirus 6B U11 and U90

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