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    ABSTRACT: Evasion of immune T cell responses is crucial for persistent viruses to establish normal carrier state. Most studies on active immune modulation mechanisms have focused on the virus production stage of the infected cells when large number of viral antigens, and potential immune-modulators, are expressed. For oncogenic viruses such as KSHV, which is carried as lifelong infections usually with little harmful effect but can cause various tumours, the immune evasion strategies can also be relevant in the context of tumourigenesis. In this study, we report that the vIRF3 latent viral gene expressed in KSHV-related tumours functions as a potent immunevasin. Expression of vIRF3 down-regulates surface MHC-II DR expression with a slow kinetics but, more importantly can substantially inhibit the recognition by KSHV-specific CD4 T cells prior to its effects on MHC-II DR down-regulation in model cell systems. This property of vIRF3 is only partly due to its ability to inhibit the transcription of CIITA, and thus MHC-II expression; CIITA-independent inhibition of MHC-II transccripts and another as yet unidentified post-transcriptional mechanism are also involved in qualitatively modulating the availability of specific peptide/MHC-II complexes at the cell surface. Consistent with these observations, the vIRF3 expressing KSHV-associated PEL lines are generally resistant to recognition by KSHV-specific CD4 T cells. Interestingly, some PEL lines exhibit small subpopulations with lower vIRF3 expression that can be recognized. These data implicate vIRF3 as a critical determinant of the MHC-II antigen presentation function in KSHV-associated PEL that is likely to be important in the pathogenesis of these tumours.
    Journal of Virology 02/2013;
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    ABSTRACT: Lifelong persistent infection by herpesviruses depends on the balance between host immune responses and viral immune evasion. CD4 T cells responding to antigens presented on major histocompatibility complex class II (MHC-II) molecules are known to play an important role in controlling herpesvirus infections. Here we review, with emphasis on human herpesvirus infections, the strategies evolved to evade CD4 T cell immunity. These viruses target multiple points on the MHC class II antigen presentation pathway. The mechanisms include: suppression of CIITA to inhibit the synthesis of MHC class II molecules, diversion or degradation of HLA-DR molecules during membrane transport, and direct targeting of the invariant chain chaperone of HLA-DR.
    Viruses 08/2012; 4(8):1335-53.
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    ABSTRACT: Evasion of immune T cell responses is crucial for viruses to establish persistence in the infected host. Immune evasion mechanisms of Epstein-Barr virus (EBV) in the context of MHC-I antigen presentation have been well studied. In contrast, viral interference with MHC-II antigen presentation is less well understood, not only for EBV but also for other persistent viruses. Here we show that the EBV encoded BZLF1 can interfere with recognition by immune CD4+ effector T cells. This impaired T cell recognition occurred in the absence of a reduction in the expression of surface MHC-II, but correlated with a marked downregulation of surface CD74 on the target cells. Furthermore, impaired CD4+ T cell recognition was also observed with target cells where CD74 expression was downregulated by shRNA-mediated inhibition. BZLF1 downregulated surface CD74 via a post-transcriptional mechanism distinct from its previously reported effect on the CIITA promoter. In addition to being a chaperone for MHC-II αβ dimers, CD74 also functions as a surface receptor for macrophage Migration Inhibitory Factor and enhances cell survival through transcriptional upregulation of Bcl-2 family members. The immune-evasion function of BZLF1 therefore comes at a cost of induced toxicity. However, during EBV lytic cycle induced by BZLF1 expression, this toxicity can be overcome by expression of the vBcl-2, BHRF1, at an early stage of lytic infection. We conclude that by inhibiting apoptosis, the vBcl-2 not only maintains cell viability to allow sufficient time for synthesis and accumulation of infectious virus progeny, but also enables BZLF1 to effect its immune evasion function.
    PLoS Pathogens 12/2011; 7(12):e1002455.
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    ABSTRACT: Despite triggering strong immune responses, Epstein-Barr virus (EBV) has colonized more than 90% of the adult human population. Successful persistence of EBV depends on the establishment of a balance between host immune responses and viral immune evasion. Here we have extended our studies on the EBV-encoded BILF1 protein, which was recently identified as an immunoevasin that functions by enhancing degradation of major histocompatibility complex class I (MHC-I) antigens via lysosomes. We now demonstrate that disruption of the EKT signaling motif of BILF1 by a K122A mutation impairs the ability of BILF1 to enhance endocytosis of surface MHC-I molecules, while subsequent lysosomal degradation was impaired by deletion of the 21-residue C-terminal tail of BILF1. Furthermore, we identified another mechanism of BILF1 immunomodulation: it targets newly synthesized MHC-I/peptide complexes en route to the cell surface. Importantly, although the diversion of MHC-I on the exocytic pathway caused a relatively modest reduction in cell surface MHC-I, presentation of endogenously processed target peptides to immune CD8(+) effector T cells was reduced by around 65%. The immune-modulating functions of BILF1 in the context of the whole virus were confirmed in cells lytically infected with a recombinant EBV in which BILF1 was deleted. This study therefore extends our initial observations on BILF1 to show that this immunoevasin can target MHC-I antigen presentation via both the exocytic and endocytic trafficking pathways. The results also emphasize the merits of including functional T cell recognition assays to gain a more complete picture of immunoevasin effects on the antigen presentation pathway.
    Journal of Virology 02/2011; 85(4):1604-14.
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    ABSTRACT: Persistent viruses have mechanisms for modulating the host immune responses that are essential for achieving a lifelong virus-host balance while minimizing the viral pathogenicity. Here we review some of the immune-modulating mechanisms evolved by the ubiquitous but potentially oncogenic Epstein-Barr virus, with particular emphasis on the molecular mechanisms of genes interfering with HLA class I antigen presentation.
    Microbes and Infection 12/2009; 12(3):173-81.
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    ABSTRACT: The increasing use of charged particle radiotherapy (CPT) in many countries will require British oncologists to establish their personal viewpoints on this subject in order to advise their patients regarding the merits or otherwise of obtaining such treatment abroad. This paper covers the advantages and some disadvantages of CPT in many anatomical locations on the basis of the achievable dose distributions as a consequence of the Bragg peak effect. The advantages in terms of normal tissue effects should follow the reduction of tissue volumes exposed to low/moderate dose: significant reductions in acute tissue effects are expected and experienced. For late reacting tissues, the predicted benefits are in the reduction of chronic low-grade symptoms and so improving the quality of life. For tumour control, dose escalation beyond what is achievable with X-ray therapy is possible only for some tumour types. Also, some tumours not presently treated by X-rays can be treated by CPT instead of radical surgery. Many of the available publications about CPT are at 'proof of principle' stage, as the treatment technique continues to be optimised: this is a similar situation to mega-voltage radiotherapy around 50 years ago. Oncologists in the UK need to familiarise themselves with CPT dose distributions, continually educate themselves by following the results of clinical studies as these emerge with time and hopefully visit CPT centres for direct experience.
    Clinical Oncology 06/2008; 20(7):555-63.
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    ABSTRACT: Unlike radical treatment protocols, in which radiobiological methods have been used in an attempt to overcome the risk of reduced tumour control, the problem of compensation for unintended treatment interruptions during palliative radiotherapy has received little attention. For palliative radiotherapy, unnecessarily extended treatment times could theoretically reduce the duration of tumour regression and symptomatic relief. It can be shown, using a simple argument, that the overall extension of the treatment time is likely to be at least equal to the reduced duration of benefit. In most practical instances, this duration would amount to relatively few days, but it can sometimes be as long as 1-2 weeks. The mechanisms for gap compensations are the same as for radical radiotherapy, although there is greater scope for hypo-fractionated compensation provided that tissue tolerances are respected. It is debatable whether compensation should be applied in all patients, but there might be clinical situations where this would be indicated. Such decisions might influence waiting times for other patients requiring radical radiotherapy, and therefore must be balanced against the available resources.
    The British journal of radiology 01/2008; 80(960):1006-10.
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    ABSTRACT: To determine the radiobiologic parameters for high-grade gliomas. The biologic effective dose concept is used to estimate the alpha/beta ratio and K (dose equivalent for tumor repopulation/d) for high-grade glioma patients treated in a randomized fractionation trial. The equivalent radiation dose of temozolomide (Temodar) chemotherapy was estimated from another randomized study. The method assumes that the radiotherapy biologic effective dose is proportional to the adjusted radiotherapy survival duration of high-grade glioma patients. The median tumor alpha/beta and K estimate is 9.32 Gy and 0.23 Gy/d, respectively. Using the published surviving fraction after 2-Gy exposure (SF2) data, and the above alpha/beta ratio, the estimated median alpha value was 0.077 Gy(-1), beta was 0.009 Gy(-2), and the cellular doubling time was 39.5 days. The median equivalent biologic effective dose of temozolomide was 11.03 Gy(9.3) (equivalent to a radiation dose of 9.1 Gy given in 2-Gy fractions). Random sampling trial simulations based on a cure threshold of 70 Gy in high-grade gliomas have shown the potential increase in tumor cure with dose escalation. Partial elimination of hypoxic cells (by chemical hypoxic cell sensitizers or carbon ion therapy) has suggested that considerable gains in tumor control, which are further supplemented by temozolomide, are achievable. The radiobiologic parameters for human high-grade gliomas can be estimated from clinical trials and could be used to inform future clinical trials, particularly combined modality treatments with newer forms of radiotherapy. Other incurable cancers should be studied using similar radiobiologic analysis.
    International Journal of Radiation OncologyBiologyPhysics 07/2007; 68(2):441-8.
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    ABSTRACT: To advance occupant protection through the improvement of safety countermeasures, it is necessary to understand the factors that affect human injury tolerance. This study investigated the effect of 'occupant factors' i.e. age, gender, height, weight, and body mass index (BMI) on the pattern of lower extremity injury after motor vehicle crashes (MVCs). The second objective was to identify factor(s) (including restraint systems and Delta V) that influence the severity of fractures (open versus close fractures) within the lower extremity area. The outcome of this study may have implications toward secondary prevention in MVCs. One-hundred and thirty-seven front-seat occupants involved in MVCs with frontal impact admitted to the University of Michigan trauma center as part of the Crash Injury Research and Engineering Network (CIREN) project were evaluated. Injuries were classified according to location (knee, thigh, hip [KTH]; lower leg [LL], foot and ankle [FA]). All the relevant variables mentioned above were analyzed. KTH fractures were the most common region (49.5%) affected, followed by fractures to the FA (38.4%) and LL region (12.1%). Female occupants, being generally shorter than their male counterpart, sustained a significantly higher percentage of FA fractures (44% vs. 29.5%, p < 0.05). Male occupants sustained more KTH fractures (58.3% vs. 44%, p < 0.05). Results demonstrated that there were significantly higher percentages of 'open' fractures in the below knee area (FA [53.8%], LL [24.4%], and KTH [21.8%]; p < 0.05). Of all those variables tested (age, gender, height, weight, BMI, restraint systems, and Delta V), occupant's height had a significant effect on the severity of fractures sustained. The interactive effect observed for height and gender on the pattern of lower extremity fracture is principally related to the body habitus and that gender may be a 'proxy' variable. The 'human factor' plays a vital role in influencing the pattern of injury in a MVC. This study strongly supports the fact that occupants with dissimilar body habitus interact differently with the interior cabin of the vehicle, thus, the performance of the active and passive safety systems.
    The Journal of trauma 03/2007; 62(3):720-9.
  • British Journal of Radiology 05/2006; 79(940):278-84.
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