35 results found
Bridges R, Correia S, Wegner F, et al., Essential role of inverted repeat in Epstein-Barr Virus IR-1 in B cell transformation; geographic variation of the viral genome, Philosophical Transactions B: Biological Sciences, ISSN: 0962-8436
Many regions of the Epstein‐Barr virus (EBV) genome, repeated and unique sequences, contribute to the geographic variation observed between strains. Here we use a large alignment of curated EBV genome sequences to identify major sites of variation in the genome of type 1 EBV strains; the CAO deletion in latent membrane protein 1 (LMP1) is the most frequent major indel present in the unique regions of EBV strains from various parts of the world. Principal component analysis was used to identify patterns of sequence variation and nucleotide positions in the sequences which can distinguish EBV from some different geographic regions. Viral genome sequence variation also affects interpretation of genetic content; known genes, origins of replication and gene expression control regions explain most of the viral genome but there are still a few sections of unknown function. One of these EBV genome regions contains a large inverted repeat sequence (invR) within the IR‐1 major internal repeat array. We deleted this invR sequence and showed that this abolished the ability of the virus to transform human B cells into lymphoblastoid cell lines.
Correia S, Bridges R, Wegner F, et al., 2018, Sequence variation of Epstein-Barr virus: viral types, geography, codon usage and diseases, Journal of Virology, Vol: 92, ISSN: 1098-5514
138 new Epstein-Barr virus (EBV) genome sequences have been determined. 125 of these and 116 from previous reports were combined to produce a multiple sequence alignment of 241 EBV genomes, which we have used to analyze variation within the viral genome. The type 1/type2 classification of EBV remains the major form of variation and is defined mostly by EBNA2 and EBNA3, but the type 2 SNPs at the EBNA3 locus extend into the adjacent gp350 and gp42 genes, whose products mediate infection of B cells by EBV. A small insertion within the BART miRNA region of the genome was present in 21 EBV strains. EBV from saliva of USA patients with chronic active EBV infection aligned with the wild type EBV genome, with no evidence of WZhet rearrangements. The V3 polymorphism in the Zp promoter for BZLF1 was found to be frequent in nasopharyngeal carcinoma cases both from Hong Kong and Indonesia. Codon usage was found to differ between latent and lytic cycle EBV genes and the main forms of variation of the EBNA1 protein have been identified.IMPORTANCE Epstein-Barr virus causes most cases of infectious mononucleosis and post-transplant lymphoproliferative disease. It contributes to several types of cancer including Hodgkin's lymphoma, Burkitt's lymphoma, diffuse large B cell lymphoma, nasopharyngeal carcinoma and gastric carcinoma. EBV genome variation is important because some of the diseases associated with EBV have very different incidences in different populations and geographic regions - differences in the EBV genome might contribute to these diseases. Some specific EBV genome alterations that appear to be significant in EBV associated cancers are already known and current efforts to make an EBV vaccine and antiviral drugs should also take account of sequence differences in the proteins used as targets.
Styles CT, Paschos K, White R, et al., 2018, The cooperative functions of the EBNA3 Proteins are central to EBV persistence and latency, Pathogens, Vol: 31, ISSN: 2076-0817
The Epstein–Barr nuclear antigen 3 (EBNA3) family of proteins, comprising EBNA3A, EBNA3B, and EBNA3C, play pivotal roles in the asymptomatic persistence and life-long latency of Epstein–Barr virus (EBV) in the worldwide human population. EBNA3-mediated transcriptional reprogramming of numerous host cell genes promotes in vitro B cell transformation and EBV persistence in vivo. Despite structural and sequence similarities, and evidence of substantial cooperative activity between the EBNA3 proteins, they perform quite different, often opposing functions. Both EBNA3A and EBNA3C are involved in the repression of important tumour suppressive pathways and are considered oncogenic. In contrast, EBNA3B exhibits tumour suppressive functions. This review focuses on how the EBNA3 proteins achieve the delicate balance required to support EBV persistence and latency, with emphasis on the contribution of the Allday laboratory to the field of EBNA3 biology.
Szymula A, Palermo RD, Bayoumy A, et al., 2018, Epstein-Barr virus nuclear antigen EBNA-LP is essential for transforming naive B cells, and facilitates recruitment of transcription factors to the viral genome, PLoS Pathogens, Vol: 14, ISSN: 1553-7366
The Epstein-Barr virus (EBV) nuclear antigen leader protein (EBNA-LP) is the first viral latency-associated protein produced after EBV infection of resting B cells. Its role in B cell transformation is poorly defined, but it has been reported to enhance gene activation by the EBV protein EBNA2 in vitro. We generated EBNA-LP knockout (LPKO) EBVs containing a STOP codon within each repeat unit of internal repeat 1 (IR1). EBNA-LP-mutant EBVs established lymphoblastoid cell lines (LCLs) from adult B cells at reduced efficiency, but not from umbilical cord B cells, which died approximately two weeks after infection. Adult B cells only established EBNA-LP-null LCLs with a memory (CD27+) phenotype. Quantitative PCR analysis of virus gene expression after infection identified both an altered ratio of the EBNA genes, and a dramatic reduction in transcript levels of both EBNA2-regulated virus genes (LMP1 and LMP2) and the EBNA2-independent EBER genes in the first 2 weeks. By 30 days post infection, LPKO transcription was the same as wild-type EBV. In contrast, EBNA2-regulated cellular genes were induced efficiently by LPKO viruses. Chromatin immunoprecipitation revealed that EBNA2 and the host transcription factors EBF1 and RBPJ were delayed in their recruitment to all viral latency promoters tested, whereas these same factors were recruited efficiently to several host genes, which exhibited increased EBNA2 recruitment. We conclude that EBNA-LP does not simply co-operate with EBNA2 in activating gene transcription, but rather facilitates the recruitment of several transcription factors to the viral genome, to enable transcription of virus latency genes. Additionally, our findings suggest that EBNA-LP is essential for the survival of EBV-infected naïve B cells.
Ba abdullah M, Palermo RD, Palser A, et al., 2017, Heterogeneity of the Epstein-Barr virus major internal repeat reveals evolutionary mechanisms of EBV and a functional defect in the prototype EBV strain B95-8., Journal of Virology, Vol: 91, ISSN: 1098-5514
Epstein-Barr virus (EBV) is a ubiquitous pathogen of humans that can cause several types of lymphoma and carcinoma. Like other herpesviruses, EBV has diversified both through co-evolution with its host, and genetic exchange between virus strains. Sequence analysis of the EBV genome is unusually challenging, because of the large number and length of repeat regions within the virus. Here we describe the sequence assembly and analysis of the large internal repeat of EBV (IR1 or BamW repeats) from over 70 strains.Diversity of the latency protein EBNA-LP resides predominantly within the exons downstream of IR1. The integrity of the putative BWRF1 ORF is retained in over 80% of strains, and deletions truncating IR1 always spare BWRF1. Conserved regions include the IR1 latency promoter (Wp), and one zone upstream of and two within BWRF1.IR1 is heterogeneous in 70% of strains, and this heterogeneity arises from sequence exchange between strains as well as spontaneous mutation, with inter-strain recombination more common in tumour-derived viruses. This genetic exchange often incorporates regions of <1kb, and allelic gene conversion changes the frequency of small regions within the repeat, but not close to the flanks. These observations suggest that IR1 — and by extension EBV — diversifies through both recombination and breakpoint repair, while concerted evolution of IR1 is driven by gene conversion of small regions. Finally, the prototype EBV strain B95-8 contains four non-consensus variants within a single IR1 repeat unit, including a STOP codon in EBNA-LP. Repairing IR1 improves EBNA-LP levels and the quality of transformation by the B95-8 BAC.
Szymula A, Palermo RD, Groves IJ, et al., 2017, Epstein-Barr virus nuclear antigen EBNA-LP is essential for transforming naive B cells, and facilitates recruitment of transcription factors to the viral genome, Publisher: Cold Spring Harbor Laboratory
<jats:title>Abstract</jats:title><jats:p>The Epstein-Barr virus (EBV) nuclear antigen leader protein (EBNA-LP) is the first viral latency-associated protein produced after EBV infection of resting B cells. Its role in B cell transformation is poorly defined, but it is reported to enhance gene activation by the EBV protein EBNA2 in vitro.</jats:p><jats:p>We generated two sets of EBNA-LP knockout (LPKO) EBVs containing a STOP codon within each repeat unit of IR1. Intronic mutations in the first of these knockouts suggested a role for the EBV sisRNAs in transformation. LPKOs with intact introns established lymphoblastoid cell lines (LCLs) from adult B cells at reduced efficiency, but umbilical cord B cells, and naive (IgD+, CD27-) adult B cells consistently died approximately two weeks after infection with LPKO, failing to establish LCLs.</jats:p><jats:p>Quantitative PCR analysis of virus gene expression after infection identified both an altered ratio of the EBNA genes, and a dramatic reduction in transcript levels of both EBNA2-regulated virus genes (LMP1 and LMP2) and the EBNA2-independent EBER genes, particularly in the first 1-2 weeks. By 30 days post infection, these levels had equalised. In contrast, EBNA2-regulated host genes were induced efficiently by LPKO viruses. Chromatin immunoprecipitation revealed that recruitment of EBNA2 and the host factors EBF1 and RBPJ to all latency promoters tested was severely delayed, whereas these same factors were recruited efficiently to several host genes, some of which exhibited increased EBNA2 recruitment.</jats:p><jats:p>We conclude that EBNA-LP does not simply co-operate with EBNA2 in activating gene transcription, but rather facilitates the recruitment of several transcription factors to the viral genome, to enable transcription of virus latency genes. Additionally, our findings suggest that different properties of EBV may have differing importance in transforming d
Styles CT, Bazot Q, Parker GA, et al., 2017, EBV epigenetically suppresses the B cell-to-plasma cell differentiation pathway while establishing long-term latency, PLoS Biology, Vol: 15, ISSN: 1544-9173
Mature human B cells infected by Epstein-Barr virus (EBV) become activated, grow, andproliferate. If the cells are infected ex vivo, they are transformed into continuously proliferatinglymphoblastoid cell lines (LCLs) that carry EBV DNA as extra-chromosomal episomes,express 9 latency-associated EBV proteins, and phenotypically resemble antigen-activatedB-blasts. In vivo similar B-blasts can differentiate to become memory B cells (MBC), inwhich EBV persistence is established. Three related latency-associated viral proteinsEBNA3A, EBNA3B, and EBNA3C are transcription factors that regulate a multitude of cellulargenes. EBNA3B is not necessary to establish LCLs, but EBNA3A and EBNA3C arerequired to sustain proliferation, in part, by repressing the expression of tumour suppressorgenes. Here we show, using EBV-recombinants in which both EBNA3A and EBNA3C canbe conditionally inactivated or using virus completely lacking the EBNA3 gene locus, that—after a phase of rapid proliferation—infected primary B cells express elevated levels of factorsassociated with plasma cell (PC) differentiation. These include the cyclin-dependentkinase inhibitor (CDKI) p18INK4c, the master transcriptional regulator of PC differentiation Blymphocyte-induced maturation protein-1 (BLIMP-1), and the cell surface antigens CD38and CD138/Syndecan-1. Chromatin immunoprecipitation sequencing (ChIP-seq) and chromatinimmunoprecipitation quantitative PCR (ChIP-qPCR) indicate that in LCLs inhibition ofCDKN2C (p18INK4c) and PRDM1 (BLIMP-1) transcription results from direct binding ofEBNA3A and EBNA3C to regulatory elements at these loci, producing stable reprogramming.Consistent with the binding of EBNA3A and/or EBNA3C leading to irreversible epigeneticchanges, cells become committed to a B-blast fate <12 days post-infection and areunable to de-repress p18INK4c or BLIMP-1—in either newly infected cells or conditionalLCLs—by inactivating EBNA3A and EBNA3C. In vitro, about 20 days aft
McHugh D, Caduff N, Barros MHM, et al., 2017, Persistent KSHV Infection Increases EBV-Associated Tumor Formation In Vivo via Enhanced EBV Lytic Gene Expression, CELL HOST & MICROBE, Vol: 22, Pages: 61-73.e7, ISSN: 1931-3128
The human tumor viruses Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) establish persistent infections in B cells. KSHV is linked to primary effusion lymphoma (PEL), and 90% of PELs also contain EBV. Studies on persistent KSHV infection in vivo and the role of EBV co-infection in PEL development have been hampered by the absence of small animal models. We developed mice reconstituted with human immune system components as a model for KSHV infection and find that EBV/KSHV dual infection enhanced KSHV persistence and tumorigenesis. Dual-infected cells displayed a plasma cell-like gene expression pattern similar to PELs. KSHV persisted in EBV-transformed B cells and was associated with lytic EBV gene expression, resulting in increased tumor formation. Evidence of elevated lytic EBV replication was also found in EBV/KSHV dually infected lymphoproliferative disorders in humans. Our data suggest that KSHV augments EBV-associated tumorigenesis via stimulation of lytic EBV replication.
Correia S, Palser A, Elgueta Karstegl C, et al., 2017, Natural variation of Epstein-Barr virus genes, proteins and pri-microRNA, Journal of Virology, Vol: 91, ISSN: 1098-5514
Viral gene sequences from an enlarged set of about 200 Epstein-Barr virus (EBV) strains including many primary isolates have been used to investigate variation in key viral genetic regions, particularly LMP1, Zp, gp350, EBNA1 and the BART miRNA cluster 2. Determination of type 1 and type 2 EBV in saliva samples from people from a wide range of geographic and ethnic backgrounds demonstrates a small percentage of healthy white Caucasian British people carrying predominantly type 2 EBV. Linkage of Zp and gp350 variants to type 2 EBV is likely to be due to their genes being adjacent to the EBNA3 locus, which is one of the major determinants of the type 1/type 2 distinction. A novel classification of EBNA1 DNA binding domains named QCIGP results from phylogeny analysis of their protein sequences but is not linked to the type 1/type 2 classification. The BART cluster 2 miRNA region is classified into three major variants through SNPs in the pri-miRNA outside of the mature miRNA sequences. These SNPs can result in altered levels of expression of some miRNAs from the BART variant frequently present in Chinese and Indonesian nasopharyngeal carcinoma (NPC) samples. The EBV genetic variants identified here provide a basis for future more directed analysis of association of specific EBV variation with EBV biology and EBV associated diseases.IMPORTANCE Incidence of diseases associated with EBV varies greatly in different parts of the world. Relationships between EBV genome sequence variation and health, disease, geography and ethnicity of the host may thus be important for understanding the role of EBV in diseases and for development of an effective EBV vaccine. This paper provides the most comprehensive analysis so far of variation in specific EBV genes relevant to these diseases and proposed EBV vaccines. By focussing on variation in LMP1, Zp, gp350, EBNA1 and the BART miRNA cluster 2, new relationships to the known type 1/type 2 strains are demonstrated and novel classificati
Palser AL, Grayson NE, White RE, et al., 2015, Genome Diversity of Epstein-Barr Virus from Multiple Tumor Types and Normal Infection, Journal of Virology, Vol: 89, Pages: 5222-5237, ISSN: 1098-5514
Epstein-Barr virus (EBV) infects most of the world’s population and is causally associated with several human cancers, but littleis known about how EBV genetic variation might influence infection or EBV-associated disease. There are currently no publishedwild-type EBV genome sequences from a healthy individual and very few genomes from EBV-associated diseases. We havesequenced 71 geographically distinct EBV strains from cell lines, multiple types of primary tumor, and blood samples and thefirst EBV genome from the saliva of a healthy carrier. We show that the established genome map of EBV accurately represents allstrains sequenced, but novel deletions are present in a few isolates. We have increased the number of type 2 EBV genomes sequencedfrom one to 12 and establish that the type 1/type 2 classification is a major feature of EBV genome variation, definedalmost exclusively by variation of EBNA2 and EBNA3 genes, but geographic variation is also present. Single nucleotide polymorphism(SNP) density varies substantially across all known open reading frames and is highest in latency-associated genes. SomeT-cell epitope sequences in EBNA3 genes show extensive variation across strains, and we identify codons under positive selection,both important considerations for the development of vaccines and T-cell therapy. We also provide new evidence for recombinationbetween strains, which provides a further mechanism for the generation of diversity. Our results provide the firstglobal view of EBV sequence variation and demonstrate an effective method for sequencing large numbers of genomes to furtherunderstand the genetics of EBV infection.
Allday MJ, Bazot Q, White RE, 2015, The EBNA3 Family: Two Oncoproteins and a Tumour Suppressor that Are Central to the Biology of EBV in B Cells, EPSTEIN BARR VIRUS, VOL 2: ONE HERPES VIRUS: MANY DISEASES, Vol: 391, Pages: 61-117, ISSN: 0070-217X
Skalska L, White RE, Parker GA, et al., 2013, Correction: Induction of p16INK4aIs the Major Barrier to Proliferation when Epstein-Barr Virus (EBV) Transforms Primary B Cells into Lymphoblastoid Cell Lines, PLoS Pathogens, Vol: 9
Skalska L, White RE, Parker GA, et al., 2013, Induction of p16(INK4a) is the major barrier to proliferation when Epstein-Barr virus (EBV) transforms primary B cells into lymphoblastoid cell lines., PLoS Pathog, Vol: 9
To explore the role of p16(INK4a) as an intrinsic barrier to B cell transformation by EBV, we transformed primary B cells from an individual homozygous for a deletion in the CDKN2A locus encoding p16(INK4a) and p14(ARF). Using recombinant EBV-BAC viruses expressing conditional EBNA3C (3CHT), we developed a system that allows inactivation of EBNA3C in lymphoblastoid cell lines (LCLs) lacking active p16(INK4a) protein but expressing a functional 14(ARF)-fusion protein (p14/p16). The INK4a locus is epigenetically repressed by EBNA3C--in cooperation with EBNA3A--despite the absence of functional p16(INK4a). Although inactivation of EBNA3C in LCLs from normal B cells leads to an increase in p16(INK4a) and growth arrest, EBNA3C inactivation in the p16(INK4a)-null LCLs has no impact on the rate of proliferation, establishing that the repression of INK4a is a major function of EBNA3C in EBV-driven LCL proliferation. This conditional LCL system allowed us to use microarray analysis to identify and confirm genes regulated specifically by EBNA3C, independently of proliferation changes modulated by the p16(INK4a)-Rb-E2F axis. Infections of normal primary B cells with recombinant EBV-BAC virus from which EBNA3C is deleted or with 3CHT EBV in the absence of activating ligand 4-hydroxytamoxifen, revealed that EBNA3C is necessary to overcome an EBV-driven increase in p16(INK4a) expression and concomitant block to proliferation 2-4 weeks post-infection. If cells are p16(INK4a)-null, functional EBNA3C is dispensable for the outgrowth of LCLs.
Paschos K, Parker GA, Watanatanasup E, et al., 2012, BIM promoter directly targeted by EBNA3C in polycomb-mediated repression by EBV, NUCLEIC ACIDS RESEARCH, Vol: 40, Pages: 7233-7246, ISSN: 0305-1048
White RE, Raemer PC, Naresh KN, et al., 2012, EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors, JOURNAL OF CLINICAL INVESTIGATION, Vol: 122, Pages: 1487-1502, ISSN: 0021-9738
Yee J, White RE, Anderton E, et al., 2011, Latent Epstein-Barr Virus Can Inhibit Apoptosis in B Cells by Blocking the Induction of NOXA Expression, PLOS ONE, Vol: 6, ISSN: 1932-6203
Gregorovic G, Bosshard R, Karstegl CE, et al., 2011, Cellular Gene Expression That Correlates with EBER Expression in Epstein-Barr Virus-Infected Lymphoblastoid Cell Lines, JOURNAL OF VIROLOGY, Vol: 85, Pages: 3535-3545, ISSN: 0022-538X
Nikitin PA, Yan CM, Forte E, et al., 2010, An ATM/Chk2-Mediated DNA Damage-Responsive Signaling Pathway Suppresses Epstein-Barr Virus Transformation of Primary Human B Cells, CELL HOST & MICROBE, Vol: 8, Pages: 510-522, ISSN: 1931-3128
White RE, Groves IJ, Turro E, et al., 2010, Extensive Co-Operation between the Epstein-Barr Virus EBNA3 Proteins in the Manipulation of Host Gene Expression and Epigenetic Chromatin Modification, PLOS ONE, Vol: 5, ISSN: 1932-6203
Skalska L, White RE, Franz M, et al., 2010, Epigenetic Repression of p16(INK4A) by Latent Epstein-Barr Virus Requires the Interaction of EBNA3A and EBNA3C with CtBP, PLOS PATHOGENS, Vol: 6, ISSN: 1553-7366
Paschos K, Smith P, Anderton E, et al., 2009, Epstein-Barr Virus Latency in B Cells Leads to Epigenetic Repression and CpG Methylation of the Tumour Suppressor Gene Bim, PLOS PATHOGENS, Vol: 5, ISSN: 1553-7366
Macnab S, White R, Hiscox J, et al., 2008, Production of an infectious Herpesvirus saimiri-based episomally maintained amplicon system, JOURNAL OF BIOTECHNOLOGY, Vol: 134, Pages: 287-296, ISSN: 0168-1656
Young P, Anderton E, Paschos K, et al., 2008, Epstein-Barr virus nuclear antigen (EBNA) 3A induces the expression of and interacts with a subset of chaperones and co-chaperones, JOURNAL OF GENERAL VIROLOGY, Vol: 89, Pages: 866-877, ISSN: 0022-1317
Macnab S, White R, Hiscox J, et al., 2008, Production of an infectious herpesvirus saimiri-based episomally maintained amplicon system, 5th Annual Conference of the British-Society-for-Gene-Therapy, Publisher: MARY ANN LIEBERT INC, Pages: 416-416, ISSN: 1043-0342
Anderton E, Yee J, Smith P, et al., 2008, Two Epstein-Barr virus (EBV) oncoproteins cooperate to repress expression of the proapoptotic tumour-suppressor Bim: clues to the pathogenesis of Burkitt's lymphoma, ONCOGENE, Vol: 27, Pages: 421-433, ISSN: 0950-9232
White RE, Carline L, Aday MJ, 2007, Mutagenesis of the herpesvirus saimiri terminal repeat region reveals important elements for virus production, JOURNAL OF VIROLOGY, Vol: 81, Pages: 6765-6770, ISSN: 0022-538X
Amon W, White RE, Farrell PJ, 2006, Epstein-Barr virus origin of lytic replication mediates association of replicating episomes with promyelocytic leukaemia protein nuclear bodies and replication compartments, JOURNAL OF GENERAL VIROLOGY, Vol: 87, Pages: 1133-1137, ISSN: 0022-1317
Calderwood M, White RE, Griffiths RA, et al., 2005, Open reading frame 73 is required for herpesvirus saimiri A11-S4 episomal persistence, JOURNAL OF GENERAL VIROLOGY, Vol: 86, Pages: 2703-2708, ISSN: 0022-1317
Calderwood MA, White RE, Whitehouse A, 2004, Development of herpesvirus-based episomally maintained gene delivery vectors., Expert Opin Biol Ther, Vol: 4, Pages: 493-505, ISSN: 1471-2598
Successful gene therapy aims to deliver and express therapeutic genes to cure or slow the progression of disease. However, a major obstacle in the application of gene therapy has been the development of the vectors used to deliver heterologous DNA to the cell or tissue of choice. A number of viral- and non-viral-based vector systems have undergone clinical trials with varying success. However, at present, no vector system possesses the full complement of properties that are generally believed necessary in an ideal gene delivery system. Therefore, alongside attempts to improve current gene delivery vectors, the identification and evaluation of new viral vectors is crucial for the long-term success of gene therapy. Herpesviruses are large DNA viruses which possess a number of advantages as gene delivery vectors. These relate to an ability to package large DNA insertions and establish lifelong latent infections in which the genomic material exists as a stable episome. This review aims to highlight the potential of herpesvirus vectors, in particular an alternative vector system based on herpesvirus saimiri (HVS). HVS is capable of infecting a range of human cell lines with high efficiencies, and the viral genome persists as high copy number, circular, non-integrated episomes which segregate to progeny following cell division. This allows the virus-based vector to stably transduce a dividing cell population and provide sustained transgene expression for an extended period of time both in vitro and in vivo. Moreover, the insertion of a bacterial artificial chromosome cassette into the HVS genome simplifies the incorporation of large amounts of heterologous DNA for gene delivery. These properties offer characteristics similar to an artificial chromosome combined with an efficient delivery system and merit its continual development as a possible gene delivery vector for the future.
White RE, Calderwood MA, Whitehouse A, 2003, Generation and precise modification of a herpesvirus salmiri bacterial artificial chromosome demonstrates that the terminal repeats are required for both virus production and episomal persistence, JOURNAL OF GENERAL VIROLOGY, Vol: 84, Pages: 3393-3403, ISSN: 0022-1317
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