Pathogenicity and virulence of human T lymphotropic virus type-1 (HTLV-1) in oncogenesis: adult T-cell leukemia/lymphoma (ATLL).

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy of CD4+ T lymphocytes caused by human T lymphotropic virus type-1 (HTLV-1) infection. HTLV-1 was brought to the World Health Organization (WHO) and researchers to address its impact on global public health, oncogenicity, and deterioration of the host immune system toward autoimmunity. In a minority of the infected population (3-5%), it can induce inflammatory networks toward HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), or hijacking the infected CD4+ T lymphocytes into T regulatory subpopulation, stimulating anti-inflammatory signaling networks, and prompting ATLL development. This review critically discusses the complex signaling networks in ATLL pathogenesis during virus-host interactions for better interpretation of oncogenicity and introduces the main candidates in the pathogenesis of ATLL. At least two viral factors, HTLV-1 trans-activator protein (TAX) and HTLV-1 basic leucine zipper factor (HBZ), are implicated in ATLL manifestation, interacting with host responses and deregulating cell signaling in favor of infected cell survival and virus dissemination. Such molecules can be used as potential novel biomarkers for ATLL prognosis or targets for therapy. Moreover, the challenging aspects of HTLV-1 oncogenesis introduced in this review could open new venues for further studies on acute leukemia pathogenesis. These features can aid in the discovery of effective immunotherapies when reversing the gene expression profile toward appropriate immune responses gradually becomes attainable.

Membrane-associated and secreted forms of the Rhesus macaque rhadinovirus-encoded CD200 homologue and cellular CD200 demonstrate differential effects on Rhesus Macaque CD200 Receptor signaling and regulation of myeloid cell activation.

The CD200-CD200R pathway is involved in inhibition of immune responses, and the importance of this pathway to infectious disease is highlighted by the fact that viral CD200 (vCD200) molecules have been found to be encoded by several DNA viruses, including the human gammaherpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV), and the closely related rhesus macaque rhadinovirus (RRV). KSHV vCD200 is the most extensively studied vCD200 molecule, however, the only herpesvirus vCD200 molecule to be examined in vivo is that encoded by RRV. Our prior studies have demonstrated that RRV vCD200 is a functional CD200 homologue that is capable of affecting immune responses in vivo, and further, that RRV can express a secreted form of vCD200 (vCD200-Sec) during infection. Despite this information, RRV vCD200 has not been examined specifically for effects on RM CD200R signaling, and the functionality of vCD200-Sec has not been examined in any context. Thus, we developed an in vitro model system in which B cells expressing vCD200 were utilized to assess the effects of this molecule on the regulation of myeloid cells expressing RM CD200R, mimicking interactions that are predicted to occur in vivo Our findings suggest that RRV vCD200 can bind and induce functional signals through RM CD200R, while vCD200-Sec represents a non-functional protein incapable of affecting CD200R signaling. We also provide the first demonstration of the function of RM CD200, which appears to possess more robust signaling capabilities than RRV vCD200, and also show that KSHV vCD200 does not efficiently induce signaling via RM CD200R.IMPORTANCE Viral CD200 homologues are encoded by KSHV and the closely related RRV. Though RRV vCD200 has been examined, questions still exist in regard to the ability of this molecule to induce signaling via rhesus macaque CD200R, as well as the potential function of a secreted form of vCD200. Further, all previous in vitro studies of RRV vCD200 have utilized an Fc fusion protein to examine functionality, which does not replicate the structural properties of the membrane-associated form of vCD200 that is naturally produced during RRV infection. In this study, we demonstrate for the first time that membrane-expressed RRV vCD200 is capable of inducing signal transduction via RM CD200R, while the secreted form of vCD200 appears to be non-functional. Further, we also demonstrate that RM CD200 induces signaling via RM CD200R, and is more robust than RRV vCD200, while KSHV vCD200 does not appear to induce efficient signaling via RM CD200R.

Very high prevalence of 25-hydroxyvitamin D deficiency in 6433 UK South Asian adults: analysis of the UK Biobank Cohort.

Little research has assessed serum 25-hydroxyvitamin D (25(OH)D) concentration and its predictors in Western-dwelling South Asians in a relatively large sample size. This observational, cross-sectional analysis assessed baseline prevalence of 25(OH)D deficiency in UK-dwelling South Asians (aged 40-69 years, 2006-2010) from the UK Biobank Cohort. Serum 25(OH)D measurements were undertaken using the DiaSorin Liaison XL assay. Of 6433 South Asians with a 25(OH)D measurement, using commonly used cut-off thresholds, 55 % (n 3538) had 25(OH)D < 25 nmol/l (severe deficiency) and 92 % (n 5918) had 25(OH)D < 50 nmol/l (insufficiency). Of the participants with a measurement, 20 % (n 1287) had 25(OH)D concentration <15 nmol/l (very severe deficiency). When 824 participants with undetectable (<10 nmol/l) 25(OH)D measurements were included (total n 7257), 29 % (n 2105) had 25(OH)D < 15 nmol/l, 60 % (n 4354) had 25(OH)D < 25 nmol/l and 93 % (n 6749) had 25(OH)D < 50 nmol/l. Logistic regression predictors of 25(OH)D < 25 nmol/l included the following characteristics: being male; Pakistani; higher BMI; 40-59 years old; never consuming oily fish; summer sun exposure <5 h/d, not using a vitamin D-containing supplement, measurement in winter or spring and vegetarianism. In terms of region, median 25(OH)D concentration was 19-20 nmol/l in Scotland, Northern England, the Midlands and Wales. Across Southern England and London, it was slightly higher at 24-25 nmol/l. Our analyses suggest the need for increased awareness of vitamin D deficiency in South Asians as well as urgent public health interventions to prevent and treat vitamin D deficiency in this group.

Merkel Cell Polyomavirus Small T Antigen Drives Cell Motility via Rho-GTPase-Induced Filopodium Formation.

Cell motility and migration is a complex, multistep, and multicomponent process intrinsic to progression and metastasis. Motility is dependent on the activities of integrin receptors and Rho family GTPases, resulting in the remodeling of the actin cytoskeleton and formation of various motile actin-based protrusions. Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high likelihood of recurrence and metastasis. Merkel cell polyomavirus (MCPyV) is associated with the majority of MCC cases, and MCPyV-induced tumorigenesis largely depends on the expression of the small tumor antigen (ST). Since the discovery of MCPyV, a number of mechanisms have been suggested to account for replication and tumorigenesis, but to date, little is known about potential links between MCPyV T antigen expression and the metastatic nature of MCC. Previously, we described the action of MCPyV ST on the microtubule network and how it impacts cell motility and migration. Here, we demonstrate that MCPyV ST affects the actin cytoskeleton to promote the formation of filopodia through a mechanism involving the catalytic subunit of protein phosphatase 4 (PP4C). We also show that MCPyV ST-induced cell motility is dependent upon the activities of the Rho family GTPases Cdc42 and RhoA. In addition, our results indicate that the MCPyV ST-PP4C interaction results in the dephosphorylation of ß1 integrin, likely driving the cell motility pathway. These findings describe a novel mechanism by which a tumor virus induces cell motility, which may ultimately lead to cancer metastasis, and provides opportunities and strategies for targeted interventions for disseminated MCC.IMPORTANCE Merkel cell polyomavirus (MCPyV) is the most recently discovered human tumor virus. It causes the majority of cases of Merkel cell carcinoma (MCC), an aggressive skin cancer. However, the molecular mechanisms implicating MCPyV-encoded proteins in cancer development are yet to be fully elucidated. This study builds upon our previous observations, which demonstrated that the MCPyV ST antigen enhances cell motility, providing a potential link between MCPyV protein expression and the highly metastatic nature of MCC. Here, we show that MCPyV ST remodels the actin cytoskeleton, promoting the formation of filopodia, which is essential for MCPyV ST-induced cell motility, and we also implicate the activity of specific Rho family GTPases, Cdc42 and RhoA, in these processes. Moreover, we describe a novel mechanism for the activation of Rho-GTPases and the cell motility pathway due to the interaction between MCPyV ST and the cellular phosphatase catalytic subunit PP4C, which leads to the specific dephosphorylation of ß1 integrin. These findings may therefore provide novel strategies for therapeutic intervention for disseminated MCC.

Vitamin D supplement use and associated demographic, dietary and lifestyle factors in 8024 South Asians aged 40-69 years: analysis of the UK Biobank cohort.

OBJECTIVE: Vitamin D deficiency (serum 25-hydroxyvitamin D<25nmol/L) is extremely common in western-dwelling South Asians but evidence regarding vitamin D supplement usage in this group is very limited. This work identifies demographic, dietary and lifestyle predictors associated with vitamin D supplement use. DESIGN: Cross-sectional analysis of baseline vitamin D supplement use data. SETTING: UK Biobank cohort. SUBJECTS: In total, n 8024 South Asians (Bangladeshi, Indian, Pakistani), aged 40-69 years. RESULTS: Twenty-three % of men and 39% of women (P<0.001) [22% of Bangladeshis, 32% of Indians, 25% of Pakistanis (P<0.001)] took a vitamin D containing supplement. Median vitamin D intakes from diet were low at 1.0-3.0 micrograms per day, being highest in Bangladeshis and lowest in Indians (P<0.001). Logistic regression modelling showed that females had a higher odds of vitamin D supplement use than males (odds ratio (OR) = 2.02; 95% confidence interval (CI) 1.79 to 2.28). A lower supplement usage was seen in younger persons (40-60 years) (OR=0.75; 95% CI 0.65 to 0.86 reference= >60 years), and those living outside of Greater London (OR=0.53 to 0.77), with borderline trends for a lower body mass index, higher oily fish intake and higher household income associated with increased odds of vitamin D supplement use. CONCLUSIONS: Vitamin D supplements were not used by most South Asians and intakes from diet alone are likely to be insufficient to maintain adequate vitamin D status. Public health strategies are now urgently required to promote the use of vitamin D supplements in these specific UK South Asian subgroups.

Functional analysis of Kaposi's sarcoma-associated herpesvirus vFLIP expression reveals a new mode of IRES-mediated translation.

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus, the etiological agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). One of the key viral proteins that contributes to tumorigenesis is vFLIP, a viral homolog of the FLICE inhibitory protein. This KSHV protein interacts with the NFκB pathway to trigger the expression of antiapoptotic and proinflammatory genes and ultimately leads to tumor formation. The expression of vFLIP is regulated at the translational level by an internal ribosomal entry site (IRES) element. However, the precise mechanism by which ribosomes are recruited internally and the exact location of the IRES has remained elusive. Here we show that a 252-nt fragment directly upstream of vFLIP, within a coding region, directs translation. We have established its RNA structure and demonstrate that IRES activity requires the presence of eIF4A and an intact eIF4G. Furthermore, and unusually for an IRES, eIF4E is part of the complex assembled onto the vFLIP IRES to direct translation. These molecular interactions define a new paradigm for IRES-mediated translation.

Merkel cell polyomavirus small T antigen mediates microtubule destabilization to promote cell motility and migration.

UNLABELLED: Merkel cell carcinoma (MCC) is an aggressive skin cancer of neuroendocrine origin with a high propensity for recurrence and metastasis. Merkel cell polyomavirus (MCPyV) causes the majority of MCC cases due to the expression of the MCPyV small and large tumor antigens (ST and LT, respectively). Although a number of molecular mechanisms have been attributed to MCPyV tumor antigen-mediated cellular transformation or replication, to date, no studies have investigated any potential link between MCPyV T antigen expression and the highly metastatic nature of MCC. Here we use a quantitative proteomic approach to show that MCPyV ST promotes differential expression of cellular proteins implicated in microtubule-associated cytoskeletal organization and dynamics. Intriguingly, we demonstrate that MCPyV ST expression promotes microtubule destabilization, leading to a motile and migratory phenotype. We further highlight the essential role of the microtubule-associated protein stathmin in MCPyV ST-mediated microtubule destabilization and cell motility and implicate the cellular phosphatase catalytic subunit protein phosphatase 4C (PP4C) in the regulation of this process. These findings suggest a possible molecular mechanism for the highly metastatic phenotype associated with MCC. IMPORTANCE: Merkel cell polyomavirus (MCPyV) causes the majority of cases of Merkel cell carcinoma (MCC), an aggressive skin cancer with a high metastatic potential. However, the molecular mechanisms leading to virally induced cancer development have yet to be fully elucidated. In particular, no studies have investigated any potential link between the virus and the highly metastatic nature of MCC. We demonstrate that the MCPyV small tumor antigen (ST) promotes the destabilization of the host cell microtubule network, which leads to a more motile and migratory cell phenotype. We further show that MCPyV ST induces this process by regulating the phosphorylation status of the cellular microtubule-associated protein stathmin by its known association with the cellular phosphatase catalytic subunit PP4C. These findings highlight stathmin as a possible biomarker of MCC and as a target for novel antitumoral therapies.

An analysis of the function and expression of D6 on lymphatic endothelial cells.

The mechanisms by which CC chemokine receptor (CCR)7 ligands are selectively presented on lymphatic endothelium in the presence of inflammatory chemokines are poorly understood. The chemokine-scavenging receptor D6 is expressed on lymphatic endothelial cells (LEC) and contributes to selective presentation of CCR7 ligands by suppressing inflammatory chemokine binding to LEC surfaces. As well as preventing inappropriate inflammatory cell attachment to LECs, D6 is specifically involved in regulating the ability of LEC to discriminate between mature and immature dendritic cells (DCs). D6 overexpression reduces immature DC (iDC) adhesion to LECs, whereas D6 knockdown increases adhesion of iDCs that displace mature DCs. LEC D6 expression is regulated by growth factors, cytokines, and tumor microenvironments. In particular, interleukin-6 and interferon-γ are potent inducers, indicating a preferential role for D6 in inflamed contexts. Expression of the viral interleukin-6 homolog from Kaposi sarcoma-associated herpesvirus is also sufficient to induce significant D6 upregulation both in vitro and in vivo, and Kaposi sarcoma and primary effusion lymphoma cells demonstrate high levels of D6 expression. We therefore propose that D6, which is upregulated in both inflammatory and tumor contexts, is an essential regulator of inflammatory leukocyte interactions with LECs and is required for immature/mature DC discrimination by LECs.

The viral interferon regulatory factors of kaposi's sarcoma-associated herpesvirus differ in their inhibition of interferon activation mediated by toll-like receptor 3.

Kaposi's sarcoma-associated herpesvirus (KSHV) infection is correlated with three human malignancies and can establish lifelong latent infection in multiple cell types within its human host. In order to establish and maintain infection, KSHV utilizes multiple mechanisms to evade the host immune response. One such mechanism is the expression of a family of genes with homology to cellular interferon (IFN) regulatory factors (IRFs), known as viral IRFs (vIRFs). We demonstrate here that KSHV vIRF1, -2, and -3 have a differential ability to block type I interferon signaling mediated by Toll-like receptor 3 (TLR3), a receptor we have previously shown to be activated upon KSHV infection. vIRF1, -2, and -3 inhibited TLR3-driven activation of IFN transcription reporters. However, only vIRF1 and vIRF2 inhibited increases in both IFN-ß message and protein levels following TLR3 activation. The expression of vIRF1 and vIRF2 also allowed for increased replication of a virus known to activate TLR3 signaling. Furthermore, vIRF1 and vIRF2 may block TLR3-mediated signaling via different mechanisms. Altogether, this report indicates that vIRFs are able to block IFN mediated by TLRs but that each vIRF has a unique function and mechanism for blocking antiviral IFN responses.

Suppression of antigen-specific T cell responses by the Kaposi's sarcoma-associated herpesvirus viral OX2 protein and its cellular orthologue, CD200.

Regulating appropriate activation of the immune response in the healthy host despite continual immune surveillance dictates that immune responses must be either self-limiting and therefore negatively regulated following their activation or prevented from developing inappropriately. In the case of antigen-specific T cells, their response is attenuated by several mechanisms, including ligation of CTLA-4 and PD-1. Through the study of the viral OX2 (vOX2) immunoregulator encoded by Kaposi's sarcoma-associated herpesvirus (KSHV), we have identified a T cell-attenuating role both for this protein and for CD200, a cellular orthologue of the viral vOX2 protein. In vitro, antigen-presenting cells (APC) expressing either native vOX2 or CD200 suppressed two functions of cognate antigen-specific T cell clones: gamma interferon (IFN-γ) production and mobilization of CD107a, a cytolytic granule component and measure of target cell killing ability. Mechanistically, vOX2 and CD200 expression on APC suppressed the phosphorylation of ERK1/2 mitogen-activated protein kinase in responding T cells. These data provide the first evidence for a role of both KSHV vOX2 and cellular CD200 in the negative regulation of antigen-specific T cell responses. They suggest that KSHV has evolved to harness the host CD200-based mechanism of attenuation of T cell responses to facilitate virus persistence and dissemination within the infected individual. Moreover, our studies define a new paradigm in immune modulation by viruses: the provision of a negative costimulatory signal to T cells by a virus-encoded orthologue of CD200.

An interaction between KSHV ORF57 and UIF provides mRNA-adaptor redundancy in herpesvirus intronless mRNA export.

The hTREX complex mediates cellular bulk mRNA nuclear export by recruiting the nuclear export factor, TAP, via a direct interaction with the export adaptor, Aly. Intriguingly however, depletion of Aly only leads to a modest reduction in cellular mRNA nuclear export, suggesting the existence of additional mRNA nuclear export adaptor proteins. In order to efficiently export Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs from the nucleus, the KSHV ORF57 protein recruits hTREX onto viral intronless mRNAs allowing access to the TAP-mediated export pathway. Similarly however, depletion of Aly only leads to a modest reduction in the nuclear export of KSHV intronless mRNAs. Herein, we identify a novel interaction between ORF57 and the cellular protein, UIF. We provide the first evidence that the ORF57-UIF interaction enables the recruitment of hTREX and TAP to KSHV intronless mRNAs in Aly-depleted cells. Strikingly, depletion of both Aly and UIF inhibits the formation of an ORF57-mediated nuclear export competent ribonucleoprotein particle and consequently prevents ORF57-mediated mRNA nuclear export and KSHV protein production. Importantly, these findings highlight that redundancy exists in the eukaryotic system for certain hTREX components involved in the mRNA nuclear export of intronless KSHV mRNAs.

Identification of a lysosomal pathway regulating degradation of the bone morphogenetic protein receptor type II.

Bone morphogenetic proteins (BMPs) are critically involved in early development and cell differentiation. In humans, dysfunction of the bone morphogenetic protein type II receptor (BMPR-II) is associated with pulmonary arterial hypertension (PAH) and neoplasia. The ability of Kaposi sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi sarcoma and primary effusion lymphoma, to down-regulate cell surface receptor expression is well documented. Here we show that KSHV infection reduces cell surface BMPR-II. We propose that this occurs through the expression of the viral lytic gene, K5, a ubiquitin E3 ligase. Ectopic expression of K5 leads to BMPR-II ubiquitination and lysosomal degradation with a consequent decrease in BMP signaling. The down-regulation by K5 is dependent on both its RING domain and a membrane-proximal lysine in the cytoplasmic domain of BMPR-II. We demonstrate that expression of BMPR-II protein is constitutively regulated by lysosomal degradation in vascular cells and provide preliminary evidence for the involvement of the mammalian E3 ligase, Itch, in the constitutive degradation of BMPR-II. Disruption of BMP signaling may therefore play a role in the pathobiology of diseases caused by KSHV infection, as well as KSHV-associated tumorigenesis and vascular disease.

Vitamin D Status of the British African-Caribbean Residents: Analysis of the UK Biobank Cohort.

The vitamin D status of the United Kingdom (UK) African-Caribbean (AC) population remains under-researched, despite an increased risk of vitamin D deficiency due to darker skin phenotypes and living at a high latitude. This cross-sectional study explored the vitamin D status and intake of AC individuals (n = 4046 with a valid serum 25(OH)D measurement) from the UK Biobank Cohort, aged ≥40 years at baseline (2006-2010). Over one third of the population were deficient (<25 nmol/L), 41.1% were insufficient (25-50 nmol/L) and 15.9% were sufficient (>50 nmol/L). Median (IQR) 25(OH)D was 30.0 (20.9) nmol/L. Logistic regression showed that brown/black skin phenotype, winter blood draw, not consuming oily fish and not using vitamin D supplements predicted increased odds of vitamin D deficiency, whilst older age and a summer or autumn blood draw were significantly associated with reduced odds of vitamin D deficiency. Vitamin D deficiency and insufficiency were prevalent in this AC population and is of considerable concern given the individual and societal implications of increased morbidity. Public health messaging for this group should focus on year-round vitamin D supplementation and increasing intakes of culturally appropriate vitamin D-rich foods. These data also support the urgent requirement for a revised vitamin D RNI for ethnic groups.

KSHV infection drives poorly cytotoxic CD56-negative natural killer cell differentiation in vivo upon KSHV/EBV dual infection.

Herpesvirus infections shape the human natural killer (NK) cell compartment. While Epstein-Barr virus (EBV) expands immature NKG2A+ NK cells, human cytomegalovirus (CMV) drives accumulation of adaptive NKG2C+ NK cells. Kaposi sarcoma-associated herpesvirus (KSHV) is a close relative of EBV, and both are associated with lymphomas, including primary effusion lymphoma (PEL), which nearly always harbors both viruses. In this study, KSHV dual infection of mice with reconstituted human immune system components leads to the accumulation of CD56-CD16+CD38+CXCR6+ NK cells. CD56-CD16+ NK cells were also more frequently found in KSHV-seropositive Kenyan children. This NK cell subset is poorly cytotoxic against otherwise-NK-cell-susceptible and antibody-opsonized targets. Accordingly, NK cell depletion does not significantly alter KSHV infection in humanized mice. These data suggest that KSHV might escape NK-cell-mediated immune control by driving CD56-CD16+ NK cell differentiation.

Modulation of the immune system by Kaposi's sarcoma-associated herpesvirus.

The most recently identified human herpesvirus is Kaposi's sarcoma-associated herpesvirus (KSHV). It causes Kaposi's sarcoma, a tumour occurring most commonly in untreated AIDS patients and the leading cancer of men in certain parts of Africa. KSHV might also contribute to the pathogenesis of primary effusion lymphoma and multicentric Castleman's disease. The genome of KSHV contains 86 genes, almost a quarter of which encode proteins with either demonstrated or potential immunoregulatory activity. They include homologues of cellular proteins and unique KSHV proteins that can deregulate many aspects of the immune response, including T- and B-cell functions, complement activation, the innate antiviral interferon response and natural killer cell activity. The functions of these proteins and the ways in which they perturb the normal immune response are the subjects of the present review.

Separation of decay-accelerating and cofactor functional activities of Kaposi's sarcoma-associated herpesvirus complement control protein using monoclonal antibodies.

Complement is an essential part of the innate immune system, which clears pathogens without requirement for previous exposure, although it also greatly enhances the efficacy and response of the cellular and humoral immune systems. Kaposi's sarcoma-associated herpesvirus (KSHV) is the most recently identified human herpesvirus and the likely aetiological agent of Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. We previously reported that the KSHV complement control protein (KCP) was expressed on infected cells and virions, and could inhibit complement through decay-accelerating activity (DAA) of the classical C3 convertase and cofactor activity (CFA) for factor I (FI)-mediated degradation of C4b and C3b, as well as acting as an attachment factor for binding to heparan sulphate on permissive cells. Here, we determined the ability of a panel of monoclonal anti-KCP antibodies to block KCP functions relative to their recognized epitopes, as determined through binding to recombinant KCP containing large (entire domain) or small (2-3 amino acid residue) alterations. One antibody recognizing complement control protein (CCP) domain 1 blocked heparin binding, DAA and C4b CFA, but was poor at blocking C3b CFA, while a second antibody recognizing CCP4 blocked C3b CFA and 80% DAA, but not C4b CFA or heparan sulphate binding. Two antibodies recognizing CCP2 and CCP3 were capable of blocking C3b and C4b CFA and heparan sulphate binding, but only one could inhibit DAA. These results show that, while KCP is a multifunctional protein, these activities do not completely overlap and can be isolated through incubation with monoclonal antibodies.

HIV Tat-mediated transcriptional regulation of proteasome protein cleavage specificity.

The major antigen-adapted immune response protecting a vertebrate against virus infection is that mediated by CTLs (cytotoxic T-lymphocytes). CTLs destroy virus-infected cells, thereby containing the infection. They are activated by recognition of peptide antigens or epitopes, presented to them in the context of MHC I proteins. These epitopes are derived from proteolytic degradation of endogenously synthesized proteins, which is mediated by the proteasome. Augmentation of epitope presentation by MHC I is thought to be effected by the immunoproteasome, induced in response to IFN-gamma (interferon-gamma) in some cells, and constitutively expressed in others. In this issue of the Biochemical Journal, Remoli and colleagues describe the manipulation of the immunoproteasome by the Tat (transcriptional activation) protein of HIV. The authors show that Tat deregulates the balance of the three proteins, LMP2 (low-molecular-mass polypeptide 2), LMP7 and MECL1 (multicatalytic endopeptidase complex-like 1), which distinguish the immunoproteasome from the proteasome, and they provide a molecular explanation. Intracellular Tat sequesters IRF-1 (interferon-regulatory factor-1) from its cognate promoter element, where normally it associates with STAT1 (signal transducer and activator of transcription 1) to activate basal transcription of the LMP2 gene. LMP2 expression is inhibited as a consequence, skewing the stoichiometry of the immunoproteasome and changing its enzymatic activity. These findings provide a molecular account of an immunomodulatory activity of HIV: changing the peptide antigen profile of cells expressing or exposed to Tat. They may also provide an avenue for manipulating vaccine efficacy and specificity with Tat-based adjuvants.

Aflatoxin B1 inhibits the type 1 interferon response pathway via STAT1 suggesting another mechanism of hepatocellular carcinoma.

BACKGROUND: Aflatoxin B1 (AFB1) contamination of food is very high in most sub-Saharan African countries. AFB1 is known to cause hepatocellular carcinoma (HCC) by inducing mutation in the tumour suppressor gene TP53. The number of new HCC cases is high in West Africa with an accompanying high mortality. The type I interferon (IFN) pathway of the innate immune system limits viral infections and exerts its anti-cancer property by up-regulating tumour suppressor activities and pro-apoptotic pathways. Indeed, IFN-α is reported to show significant protective effects against hepatic fibrogenesis and carcinogenesis. However, the mechanism behind AFB1 deregulation of the type I interferon (IFN) signalling pathway, with consequent HCC is largely unknown. This current study seeks to test the hypothesis that AFB1 inhibits the type I IFN response by directly interfering with key signalling proteins and thus increase the risk of HCC in humans. METHODS: We evaluated the effects of AFB1 on the type I IFN signalling pathway using IFN stimulated response element (ISRE)-based luciferase reporter gene assay. In addition, the effects of AFB1 on the transcript levels of JAK1, STAT1 and OAS3 were assessed by real-time quantitative polymerase chain reaction (RT-qPCR) and confirmed by immunoblot assay. RESULTS: Our results indicated that AFB1 inhibited the type I IFN signalling pathway in human hepatoma cell line HepG2 cells by suppressing the transcript levels of JAK1, STAT1 and OAS3. AFB1 also decreased the accumulation of STAT1 protein. CONCLUSION: The inhibition of the type I IFN anti-cancer response pathway by AFB1 suggest a novel mechanism by which AFB1 may induce hepatocellular carcinoma in humans.

Persistent KSHV Infection Increases EBV-Associated Tumor Formation In Vivo via Enhanced EBV Lytic Gene Expression.

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.

Inhibition of neutrophil function by the Kaposi's sarcoma-associated herpesvirus vOX2 protein.

Kaposi's sarcoma is multifactorial, involving Kaposi's sarcoma-associated herpesvirus (KSHV) infection and immune dysfunction. A KSHV protein (vOX2), fused with the Fc domain of human immunoglobulin G1 to create vOX2:Fc, suppressed neutrophil oxidative burst and inhibited the production of pro-inflammatory chemokines (IL-8 and monocyte chemoattractant protein 1) by monocyte/macrophage cells. vOX2:Fc suppressed the acute inflammatory response in mice in which neutrophil-mediated inflammation was induced by carrageenan. The data suggest that vOX2 can contribute to immune dysfunction and could have anti-inflammatory therapeutic potential.