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The ability of Epstein-Barr virus (EBV) to spread and persist in human populations relies on a balance between host immune responses and EBV immune evasion. CD8؉ cells specific for EBV late lytic cycle antigens show poor recognition of target cells compared to immediate early and early antigen-specific CD8 ؉ cells. This phenomenon is due in part to the early EBV protein BILF1, whose immunosuppressive activity increases with lytic cycle progression. However, published data suggest the existence of a hitherto unidentified immune evasion protein further enhancing protection against late EBV antigen-specific CD8 ؉ cells. We have now identified the late lytic BDLF3 gene as the missing link accounting for efficient evasion during the late lytic cycle. Interestingly, BDLF3 also contributes to evasion of CD4 ؉ cell responses to EBV. We report that BDLF3 downregulates expression of surface major histocompatibility complex (MHC) class I and class II molecules in the absence of any effect upon other surface molecules screened, including CD54 (ICAM-1) and CD71 (transferrin receptor). BDLF3 both enhanced internalization of surface MHC molecules and reduced the rate of their appearance at the cell surface. The reduced expression of surface MHC molecules correlated with functional protection against CD8؉ and CD4 ؉ T cell recognition. The molecular mechanism was identified as BDLF3-induced ubiquitination of MHC molecules and their subsequent downregulation in a proteasome-dependent manner. IMPORTANCE Immune evasion is a necessary feature of viruses that establish lifelong persistent infections in the face of strong immune responses. EBV is an important human pathogen whose immune evasion mechanisms are only partly understood. Of the EBV immune evasion mechanisms identified to date, none could explain why CD8؉ T cell responses to late lytic cycle genes are so infrequent and, when present, recognize lytically infected target cells so poorly relative to CD8 ؉ T cells specific for early lytic cycle antigens. The present work identifies an additional immune evasion protein, BDLF3, that is expressed late in the lytic cycle and impairs CD8 ؉ T cell recognition by targeting cell surface MHC class I molecules for ubiquitination and proteasome-dependent downregulation. Interestingly, BDLF3 also targets MHC class II molecules to impair CD4 ؉ T cell recognition. BDLF3 is therefore a rare example of a viral protein that impairs both the MHC class I and class II antigen-presenting pathways. E pstein-Barr virus (EBV) is a gammaherpesvirus found in more than 90% of the human population. Primary infection with EBV is usually followed by establishment of a lifelong latent infection, with occasional reactivation (1). The balance between host immune responses, including CD4 ϩ and CD8 ϩ T cells, and viral immune evasion of these responses is key to the spread and survival of EBV in human populations. Passive evasion through the ability to establish antigenically silent latent infections is an important characteristic of all herpesviruses, ...

Epstein-Barr Virus (EBV) persists for the lifetime of the infected host despite eliciting strong immune responses. This persistence requires a fine balance between the host immune system and EBV immune evasion. Accumulating evidence suggests an important role for natural killer (NK) cells in this balance. NK cells can kill EBV-infected cells undergoing lytic replication in vitro, and studies in both humans and mice with reconstituted human immune systems have shown that NK cells can limit EBV replication and prevent infectious mononucleosis. We now show that NK cells, via NKG2D and DNAM-1 interactions, recognize and kill EBV-infected cells undergoing lytic replication and that expression of a single EBV lytic gene, BZLF1, is sufficient to trigger sensitization to NK cell killing. We also present evidence suggesting the possibility of the existence of an as-yet-unidentified DNAM-1 ligand which may be particularly important for killing lytically infected normal B cells. Furthermore, while cells entering the lytic cycle become sensitized to NK cell killing, we observed that cells in the late lytic cycle are highly resistant. We identified expression of the vBcl-2 protein, BHRF1, as one effective mechanism by which EBV mediates this protection. Thus, contrary to the view expressed in some reports, EBV has evolved the ability to evade NK cell responses. IMPORTANCEThis report extends our understanding of the interaction between EBV and host innate responses. It provides the first evidence that the susceptibility to NK cell lysis of EBV-infected B cells undergoing lytic replication is dependent upon the phase of the lytic cycle. Induction of the lytic cycle is associated with acquired sensitization to NK cell killing, while progress through the late lytic cycle is associated with acquired resistance to killing. We provide mechanistic explanations for this novel observation, indicating important roles for the BZLF1 immediate early transactivator, the BHRF1 vBcl-2 homologue, and a novel ligand for the DNAM-1 NK cell receptor. E pstein-Barr Virus (EBV), one of eight human herpesviruses, is carried by over 90% of the world's adult population. Primary EBV infection occurs in the oropharynx, leading to infection of B lymphocytes (1, 2). These infected B cells can support the lytic cycle, in which more than 80 viral genes are expressed to generate new infectious virus, but they more frequently host nonproductive infections through expression of a limited number of socalled latent EBV genes (latency III genes) that drive lymphoproliferation as an alternative mechanism of expanding the infected cell pool. In vitro, this growth transformation is demonstrated by the ready establishment of lymphoblastoid cell lines (LCLs) following infection of resting B cells. Following initial infection in vivo, EBV downregulates the expression of all viral proteins and enters a true latent phase (latency 0) in the memory B cell population, where it establishes a lifelong infection (1). Periodically the virus reactivates and undergoes fu...

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SUMMARYFull thickness calvarial defects present considerable challenges to reconstructive surgeons. In paediatric cases, the use of biomaterials as a substrate for cranioplasty rather than autologous bone is controversial. Alloplastic cranioplasty in adults is supported by several large case series however long term outcome of biomaterial use in paediatric cases is limited. Retrospective seven year analysis of departmental database and clinical records identified 22 patients aged under 18 who had undergone 23 custom made titanium cranioplasties by a single surgeon using the same technique.Data including patient demographics, reason for craniectomy and complications experienced following surgery was obtained. The mean age at operation was 12 years 9 months. The mean defect size was 44.3cm 2 . No significant complications related to the cranioplasty were recorded in the early post operative period or during long term review (average follow up 4 years 6 months). No cranioplasty implant required removal. This retrospective case series shows that custom made patient specific titanium cranioplasty is a viable alternative to autologous bone as a reconstructive material in paediatric patients under specific circumstances.

Esophageal tumor length assessed using CT does not reflect pathological tumor extent and should not be the only modality used for management decisions, particularly for planning radiotherapy.

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The herpesviruses are a family of double-stranded DNA viruses that infect a wide variety of organisms. Having co-evolved with their hosts over millennia, herpesviruses have developed a large repertoire of mechanisms to manipulate normal cellular processes for their own benefit. Consequently, studies on these viruses have made important contributions to our understanding of fundamental biological processes. Here we describe recent research on the human herpesviruses that has contributed to our understanding of, and interactions between, viruses, autophagy, and the immune system. The ability of autophagy to degrade proteins located within the nucleus, the site of herpesvirus latency and replication, is also considered.