Epstein–Barr virus: LMP1 masquerades as an active receptor

AbstractThe Epstein–Barr virus protein LMP1 is essential for transformation of resting B cells by the virus, but how it works is unclear. Recent results suggest that LMP1 acts as a constitutively active receptor that shares certain characteristics with members of the tumour necrosis factor receptor superfamily

Numerical Simulations of Inhomogeneous Quantum Turbulence

Ph. D. Thesis.The modelling of turbulent fluids has been an active area of research for over a century, with applications in diverse areas such as aeronautics and meteorology. The discovery and realisation of quantum fluids, such as low temperature helium and Bose-Einstein condensates (BECs), o ers an experimental and theoretical route toward insights into the dynamics of classical fluids in an ostensibly simpler, due their inviscid properties, context. However, to utilise this we need to appreciate where they are comparable and where they di er signi cantly, in terms of their material properties, their flows, and any phenomena arising from the underlying quantum mechanics. The work in this thesis aims to further this understanding by considering the problem of vorticity transport, and extending previous work concerning dissipation in quantum fluids. Turbulence in classical fluids consists of vortices of many length scales, from the size of the system down to the Kolmogorov length scale at which viscosity acts to dissipate energy; the direct numerical simulation of classical flows with even moderate Reynolds numbers is extremely computationally intensive due to the need to resolve at many scales. In contrast, vortices in quantum fluids have quantised circulation, and only those quantum vortices with the lowest circulation are stable. Two distinct regimes of turbulence have been identi ed in quantum fluids, the quasiclassical regime in which organised bundles of vortex laments are believed to emulate the range of scales and energy distribution observed in classical turbulence, and the ultraquantum regime, composed of an essentially random tangle of vortices with no large-scale structure. Despite these fundamental di erences many parallels have been observed between classical turbulence and quantum turbulence, including various hydrodynamic instabilities, the development of K arm an vortex streets in the wake of barriers in a flow, and the Kolmogorov velocity statistics and energy spectrum. The numerical investigations in this thesis can be split into those pertaining to homogeneous turbulence, and those pertaining to inhomogeneous turbulence. Many experiments probe the properties of quantum turbulence in super fluid helium through channel ow experiments, with versatile theory due to Vinen (Proc. Royal Soc. Lond. A 240, 1220:114- 127 (1957)) describing the evolution of the statistical vortex line density in terms of opposing vortex generation and dissipation. We simulate homogeneous turbulence generated by thermal counter flow using the vortex lament method (VFM) in order to quantify the balance of the generation and dissipation of vorticity with an established technique. We then use a new numerical technique to probe the dissipation of homogeneous ultraquantum turbulence, by arti cally injecting random vortices to reach statistically steady states. Other experiments generate quantum turbulence locally, producing systems that are initially inhomogeneous. The behaviour of inhomogeneous quantum turbulence is less well understood than in the homogeneous case, and we address how vorticity spreads in such systems. We rst consider the problem in systems of reduced dimensionality, relevant to BECs in which strong con nement in one direction results in quasi-2-D condensates. In these systems vortices are essentially topological point defects, since excitations along vortex lines are suppressed in the tightly con ned direction. We model the evolution of an initially con ned region of point vortices in such a geometry using the point vortex model and the Gross-Pitaevskii equation, and identify a value for the e ective viscosity as an emergent property of the spreading of the vortices. A related investigation is performed for turbulence in super fluid 4He at zero temperature in a fully three-dimensional geometry. The dynamics of quantum vortices are modelled with the VFM, and a value for the e ective viscosity is found. We compare our method to a previous study, and review the values found for the e ective viscosity at zero temperature and nite temperatures below the lamdba-point.EPSR

CD4+ T-cell responses to Epstein-Barr virus nuclear antigen EBNA1 in Chinese populations are highly focused on novel C-terminal domain-derived epitopes

Epstein-Barr virus nuclear antigen EBNA1, the one viral protein uniformly expressed in nasopharyngeal carcinoma (NPC), represents a prime target for T-cell-based immunotherapy. However, little is known about the EBNA1 epitopes, particularly CD4 epitopes, presented by HLA alleles in Chinese people, the group at highest risk for NPC. We analyzed the CD4$^+$ T-cell responses to EBNA1 in 78 healthy Chinese donors and found marked focusing on a small number of epitopes in the EBNA1 C-terminal region, including a DP5- restricted epitope that was recognized by almost half of the donors tested and elicited responses able to recognize EBNA1-expressing, DP5-positive target cells

Epstein-Barr virus (EBV)-associated lymphoproliferative disease in the SCID mouse model: implications for the pathogenesis of EBV-positive lymphomas in man

When human peripheral blood lymphocytes (PBLs) from Epstein-Barr virus (EBV)-seropositive donors are injected intraperitoneally into SCID mice, EBV+ B cell tumors develop within weeks. A preliminary report (Mosier, D. E., R. J. Gulizia, S. M. Baird, D. D. Richman, D. B. Wilson, R. I. Fox, and T. J. Kipps, 1989. Blood. 74(Suppl. 1):52a) has suggested that such tumors resemble the EBV-positive malignancy, Burkitt's lymphoma. The present work shows that generally the human (hu) PBL-SCID tumors are distinct from Burkitt's lymphoma and instead resemble lymphoblastoid cell lines (LCLs) generated by EBV-infection of normal B cells in vitro in terms of: (a) their cell surface phenotype, with expression of B cell activation antigens and adhesion molecules, (b) normal karyotype, and (c) viral phenotype, with expression of all the transformation-associated EBV latent proteins and, in a minority of cells, productive cycle antigens. Indeed, in vitro-transformed LCLs also grow when inoculated into SCID mice, the frequency of tumor outgrowth correlating with the in vitro growth phenotype of the LCL which is itself determined by the identity of the transforming virus (i.e., type 1 or type 2 EBV). Histologically the PBL-derived hu-SCID tumors resemble the EBV+ large cell lymphomas that develop in immuno-suppressed patients and, like the human tumors, often present at multiple sites as individual monoclonal or oligoclonal foci. The remarkable efficiency of tumor development in the hu-SCID model suggests that lymphomagenesis involves direct outgrowth of EBV-transformed B cells without requirement for secondary genetic changes, and that selection on the basis of cell growth rate alone is sufficient to explain the monoclonal/oligoclonal nature of tumor foci. EBV+ large cell lymphoma of the immunosuppressed may arise in a similar way

CD4+ T-cell responses to Epstein-Barr virus (EBV) latent-cycle antigens and the recognition of EBV-transformed lymphoblastoid cell lines

There is considerable interest in the potential of Epstein-Barr virus (EBV) latent antigen-specific CD4$^+$ T cells to act as direct effectors controlling EBV-induced B lymphoproliferations. Such activity would require direct CD4$^+$ T-cell recognition of latently infected cells through epitopes derived from endogenously expressed viral proteins and presented on the target cell surface in association with HLA class II molecules. It is therefore important to know how often these conditions are met. Here we provide CD4$^+$ epitope maps for four EBV nuclear antigens, EBNA1, -2, -3A, and -3C, and establish CD4$^+$ T-cell clones against 12 representative epitopes. For each epitope we identify the relevant HLA class II restricting allele and determine the efficiency with which epitope-specific effectors recognize the autologous EBV-transformed B-lymphoblastoid cell line (LCL). The level of recognition measured by gamma interferon release was consistent among clones to the same epitope but varied between epitopes, with values ranging from 0 to 35% of the maximum seen against the epitope peptide-loaded LCL. These epitope-specific differences, also apparent in short-term cytotoxicity and longer-term outgrowth assays on LCL targets, did not relate to the identity of the source antigen and could not be explained by the different functional avidities of the CD4$^+$ clones; rather, they appeared to reflect different levels of epitope display at the LCL surface. Thus, while CD4$^+$ T-cell responses are detectable against many epitopes in EBV latent proteins, only a minority of these responses are likely to have therapeutic potential as effectors directly recognizing latently infected target cells

Immediate Early and Early Lytic Cycle Proteins Are Frequent Targets of the Epstein-Barr Virus–induced Cytotoxic T Cell Response

Epstein-Barr virus (EBV), a human γ-herpesvirus, can establish both nonproductive (latent) and productive (lytic) infections. Although the CD8+ cytotoxic T lymphocyte (CTL) response to latently infected cells is well characterized, very little is known about T cell controls over lytic infection; this imbalance in our understanding belies the importance of virus-replicative lesions in several aspects of EBV disease pathogenesis. The present work shows that the primary CD8+ CTL response to EBV in infectious mononucleosis patients contains multiple lytic antigen-specific reactivities at levels at least as high as those seen against latent antigens; similar reactivities are also detectable in CTL memory. Clonal analysis revealed individual responses to the two immediate early proteins BZLF1 and BRLF1, and to three (BMLF1, BMRF1, and BALF2) of the six early proteins tested. In several cases, the peptide epitope and HLA-restricting determinant recognized by these CTLs has been defined, one unusual feature being the number of responses restricted through HLA-C alleles. The work strongly suggests that EBVreplicative lesions are subject to direct CTL control in vivo and that immediate early and early proteins are frequently the immunodominant targets. This contrasts with findings in α- and β-herpesvirus systems (herpes simplex, cytomegalovirus) where viral interference with the antigen-processing pathway during lytic infection renders immediate early and early proteins much less immunogenic. The unique capacity of γ-herpesvirus to amplify the viral load in vivo through a latent growth-transforming infection may have rendered these agents less dependent upon viral replication as a means of successfully colonizing their hosts