Epstein-Barr Virus Latent Membrane Protein 1 Genetic Variability in Peripheral Blood B Cells and Oropharyngeal Fluids

Renzette, Nicholas; Somasundaran, Mohan; Brewster, Frank; Coderre, James A.; Weiss, Eric R.; McManus, Margaret; Greenough, Thomas C.; Tabak, Barbara; Garber, Manuel; Kowalik, Timothy F.; Luzuriaga, Katherine

doi:10.1128/jvi.03378-13

Cited by 20 publications

(21 citation statements)

References 73 publications

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“…However, the technical aspects of these papers leave much to be desired and there is a need to reproduce them using modern sensitive, quantitative techniques. This is especially true in light of recent work from the laboratory of Katherine Luzuriaga (Renzette et al 2014). They have presented intriguing evidence from deep sequencing of EBV within infected individuals that variants are primarily generated over time in saliva not in the blood.…”

Section: Other Sites Of Ebv Persistencementioning

confidence: 95%

EBV Persistence—Introducing the Virus

Thorley‐Lawson

2015

Current Topics in Microbiology and Immunology

235

347

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Persistent infection by EBV is explained by the germinal center model (GCM) which provides a satisfying and currently the only explanation for EBVs disparate biology. Since the GCM touches on every aspect of the virus, this chapter will serve as an introduction to the subsequent chapters. EBV is B lymphotropic, and its biology closely follows that of normal mature B lymphocytes. The virus persists quiescently in resting memory B cells for the lifetime of the host in a non-pathogenic state that is also invisible to the immune response. To access this compartment, the virus infects naïve B cells in the lymphoepithelium of the tonsils and activates these cells using the growth transcription program. These cells migrate to the GC where they switch to a more limited transcription program, the default program, which helps rescue them into the memory compartment where the virus persists. For egress, the infected memory cells return to the lymphoepithelium where they occasionally differentiate into plasma cells activating viral replication. The released virus can either infect more naïve B cells or be amplified in the epithelium for shedding. This cycle of infection and the quiescent state in memory B cells allow for lifetime persistence at a very low level that is remarkably stable over time. Mathematically, this is a stable fixed point where the mechanisms regulating persistence drive the state back to equilibrium when perturbed. This is the GCM of EBV persistence. Other possible sites and mechanisms of persistence will also be discussed.

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Section: Other Sites Of Ebv Persistencementioning

confidence: 95%

EBV Persistence—Introducing the Virus

Thorley‐Lawson

2015

Current Topics in Microbiology and Immunology

235

347

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“…In addition to B95.8-LMP1, a large number of LMP1 sequence variants have been isolated predominantly from NPC samples or healthy carriers of different geographical regions of the world (Hu et al 1991;Miller et al 1994;Sandvej et al 1997;Hatton et al 2014;Lorenzetti et al 2012;Renzette et al 2014). Due to space limitations, a detailed description of such LMP1 variants cannot be given here.…”

Section: Carboxy-terminal Signaling Domainmentioning

confidence: 97%

The Latent Membrane Protein 1 (LMP1)

Kieser

Sterz

2015

Current Topics in Microbiology and Immunology

120

127

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Almost exactly twenty years after the discovery of Epstein-Barr virus (EBV), the latent membrane protein 1 (LMP1) entered the EBV stage, and soon thereafter, it was recognized as the primary transforming gene product of the virus. LMP1 is expressed in most EBV-associated lymphoproliferative diseases and malignancies, and it critically contributes to pathogenesis and disease phenotypes. Thirty years of LMP1 research revealed its high potential as a deregulator of cellular signal transduction pathways leading to target cell proliferation and the simultaneous subversion of cell death programs. However, LMP1 has multiple roles beyond cell transformation and immortalization, ranging from cytokine and chemokine induction, immune modulation, the global alteration of gene and microRNA expression patterns to the regulation of tumor angiogenesis, cell-cell contact, cell migration, and invasive growth of tumor cells. By acting like a constitutively active receptor, LMP1 recruits cellular signaling molecules associated with tumor necrosis factor receptors such as tumor necrosis factor receptor-associated factor (TRAF) proteins and TRADD to mimic signals of the costimulatory CD40 receptor in the EBV-infected B lymphocyte. LMP1 activates NF-κB, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3-K), IRF7, and STAT pathways. Here, we review LMP1's molecular and biological functions, highlighting the interface between LMP1 and the cellular signal transduction network as an important factor of virus-host interaction and a potential therapeutic target.

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“…B cells were isolated from whole blood using a RosetteSep human B-cell kit (Stemcell Technologies, Vancouver, BC, Canada). DNA was extracted using a Qiagen DNeasy blood and tissue kit (Valencia, CA), and blood viral loads were measured using a Roche LightCycler EBV quantification kit (Roche, Indianapolis, IN) (17,46).…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies, including our own, have demonstrated that dsDNA viruses can exhibit levels of variation similar to those observed in some RNA viruses, such as West Nile virus and HIV-1 (16,17). Most published EBV gp350 sequences have originated from either transformed B-cell lines or cancerous tissue; at present, only a very limited number of primary EBV gp350 sequences are available (18).…”

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confidence: 99%

High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis

Weiss

Alter

Ogembo

et al. 2017

J Virol

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The Epstein-Barr virus (EBV) gp350 glycoprotein interacts with the cellular receptor to mediate viral entry and is thought to be the major target for neutralizing antibodies. To better understand the role of EBV-specific antibodies in the control of viral replication and the evolution of sequence diversity, we measured EBV gp350-specific antibody responses and sequenced the gp350 gene in samples obtained from individuals experiencing primary EBV infection (acute infectious mononucleosis [AIM]) and again 6 months later (during convalescence [CONV]). EBV gp350-specific IgG was detected in the sera of 17 (71%) of 24 individuals at the time of AIM and all 24 (100%) individuals during CONV; binding antibody titers increased from AIM through CONV, reaching levels equivalent to those in age-matched, chronically infected individuals. Antibody-dependent cell-mediated phagocytosis (ADCP) was rarely detected during AIM (4 of 24 individuals; 17%) but was commonly detected during CONV (19 of 24 individuals; 79%). The majority (83%) of samples taken during AIM neutralized infection of primary B cells; all samples obtained at 6 months postdiagnosis neutralized EBV infection of cultured and primary target cells. Deep sequencing revealed interpatient gp350 sequence variation but conservation of the CR2-binding site. The levels of gp350-specific neutralizing activity directly correlated with higher peripheral blood EBV DNA levels during AIM and a greater evolution of diversity in gp350 nucleotide sequences from AIM to CONV. In summary, we conclude that the viral load and EBV gp350 diversity during early infection are associated with the development of neutralizing antibody responses following AIM.IMPORTANCE Antibodies against viral surface proteins can blunt the spread of viral infection by coating viral particles, mediating uptake by immune cells, or blocking interaction with host cell receptors, making them a desirable component of a sterilizing vaccine. The EBV surface protein gp350 is a major target for antibodies. We report the detection of EBV gp350-specific antibodies capable of neutralizing EBV infection in vitro. The majority of gp350-directed vaccines focus on glycoproteins from lab-adapted strains, which may poorly reflect primary viral envelope diversity. We report some of the first primary gp350 sequences, noting that the gp350 host receptor binding site is remarkably stable across patients and time. However, changes in overall gene diversity were detectable during infection. Patients with higher peripheral blood viral loads in primary infection and greater changes in viral diversity generated more efficient antibodies. Our findings provide insight into the generation of functional antibodies, necessary for vaccine development.

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Epstein-Barr Virus Latent Membrane Protein 1 Genetic Variability in Peripheral Blood B Cells and Oropharyngeal Fluids

Cited by 20 publications

References 73 publications

EBV Persistence—Introducing the Virus

EBV Persistence—Introducing the Virus

The Latent Membrane Protein 1 (LMP1)

High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis

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