Search

Background: The disparity between government health expenditures across regions is more severe in developing countries than it is in developed countries. The capitation subsidy method has been proven effective in developed countries in reducing this disparity, but it has not been tested in China, the world's largest developing country.Methods: The convergence method of neoclassical economics was adopted to test the convergence of China's regional government health expenditure. Data were obtained from Provinces, Prefectures and Counties Fiscal Statistical Yearbook (2003-2007) edited by the Chinese Ministry of Finance, and published by the Chinese Finance & Economics Publishing House.Results: The existence of σ-convergence and long-term and short-term β-convergence indicated the effectiveness of the capitation subsidy method in the New Rural Cooperative Medical Scheme on narrowing county government health expenditure disparities. The supply-side variables contributed the most to the county government health expenditure convergence, and factors contributing to convergence of county government health expenditures per capita were different in three regions.Conclusion: The narrowing disparity between county government health expenditures across regions supports the effectiveness of the capitation subsidy method adopted by China's New Rural Cooperative Scheme. However, subsidy policy still requires further improvement. [ABSTRACT FROM AUTHOR]

Background: China had 236 million internal migrants in 2012 and the majority of them migrated from rural to urban areas. The research based on medical and epidemical records found that the migrants had worse health than the urban residents, but the household and working place investigations reported better health status. The sick or unhealthy migrants are likely to return to their hometowns, which in turn may cause a report bias or over-estimation of the health status of rural-to-urban migrants in China. This paper explores the association of migration status and the physical and psychological health of Chinese internal migrants. Methods: Nationally representative household survey data from the China Labor-force Dynamics Survey 2012 (CLDS) were used to analyze the association between the migration status and the health status of internal migrants in China. Migration status of the respondents was measured by hukou status and migration experience and all respondents were divided into four groups: returned population, migrant population, urban residents, and rural residents. Health status of respondents was measured by self-reported physical and psychological health. Results: Migration experience was associated with the physical health of the returned population. The physical health of the returned population was worse than the migrant population and was distinguished by age and sex. The physical health status of migrant population was significantly better than rural residents, but not significantly better than urban residents. However, the association between migration status and psychological health was not statistically significant. Besides migration status, the socioeconomic status (SES) had a positive correlation with both physical and psychological health status, while occupational hazards exerted negative influence. Conclusion: The results indicate a tight association between migration experience and health status. The internal unhealthy migrants were more likely to return to their hometown and the migrant population might have limited health advantage. [ABSTRACT FROM AUTHOR]

Development of microarray technology has resulted in an exponential rise in gene expression data. Linear computational methods are of great assistance in identifying molecular interactions, and elucidating the functional properties of gene networks. It overcomes the weaknesses of in vivo experiments including high cost, large noise, and unrepeatable process. In this paper, we propose an easily applied system, Stepwise Network Inference (SWNI), which integrates deterministic linear model with statistical analysis, and has been tested effectively on both simulated experiments and real gene expression data sets. The study illustrates that connections of gene networks can be significantly detected via SWNI with high confidence, when single gene perturbation experiments are performed complying with the algorithm requirements. In particular, our algorithm shows efficiency and outperforms the existing ones presented in this paper when dealing with large-scale sparse networks without any prior knowledge. [ABSTRACT FROM AUTHOR]

Interferon regulatory factor 7 (IRF-7) is implicated in the regulation of Epstein-Barr virus (EBV) latency. EBV transforms primary B cells, and the major EBV oncoprotein, latent membrane protein 1 (LMP-1), is required for the process. LMP-1 both induces the expression of IRF-7 and activates the IRF-7 protein by phosphorylation and nuclear translocation. Here we report that the expression of IRF-7 is increased in EBV-immortalized B lymphocytes compared with that in primary B cells. IRF-7 was phosphorylated and predominantly localized in the nucleus in the immortalized cells. The expression of IRF-7 was detected in 19 of 27 specimens of primary lymphomas of the human central nervous system by immunohistochemical analysis. The association between LMP-1 and IRF-7 was statistically highly significant for these specimens. An appreciable amount of the IRF-7 expressed in lymphoma cells was localized in the nucleus. Furthermore, IRF-7 promoted the anchorage-independent growth of NIH 3T3 cells. LMP-1 and IRF-7 showed additive effects on the growth transformation of NIH 3T3 cells. IRF-7-expressing NIH 3T3 cells formed tumors in athymic mice. Thus, IRF-7 has oncogenic properties and, along with LMP-1, may mediate or potentiate the EBV transformation process in the pathogenesis of EBV-associated lymphomas. [ABSTRACT FROM AUTHOR]

Porcine deltacoronavirus (PDCoV) is an emerging enteropathogenic coronavirus. It causes mortality in neonatal piglets and is of growing concern because of its broad host range, including humans. To date, the mechanism of PDCoV infection remains poorly understood. Here, based on a genome-wide CRISPR screen of PDCoV-infected cells, we found that HSP90AB1 (heat shock protein 90 alpha family class B1) promotes PDCoV infection. Knockdown or KO of HSP90AB1 in LLC-PK cells resulted in a significantly suppressed PDCoV infection. Infected cells treated with HSP90 inhibitors 17-AAG and VER-82576 also showed a significantly suppressed PDCoV infection, although KW-2478, which does not affect the ATPase activity of HSP90AB1, had no effect on PDCoV infection. We found that HSP90AB1 interacts with the N, NS7, and NSP10 proteins of PDCoV. We further evaluated the interaction between N and HSP90AB1 and found that the Ctail domain of the N protein is the HSP90AB1-interacting domain. Further studies showed that HSP90AB1 protects N protein from degradation via the proteasome pathway. In summary, our results reveal a key role for HSP90AB1 in the mechanism of PDCoV infection and contribute to provide new host targets for PDCoV antiviral research. [ABSTRACT FROM AUTHOR]

The article investigates the regulatory circuit between Kaposi sarcoma associated herpesvirus and host innate immune system. It found that Toll-interleukin-1 receptor domain-containing adaptor-inducing ß-interferon (TRIF) increases the expression of KSHV replication and transcription activator (RTA). It highlights the pathways of enhancement of RTA expression and degradation of TRIF.

Background: The prevalence of infection with Toxoplasma gondii (T. gondii) in humans has been increasing in China due to the growing number of cats in the country. Hand, foot and mouth disease (HFMD) is a serious public health issue in China and still one of the leading causes of child mortality. However, little is known about the epidemiology of T. gondii infection among HFMD patients. Methods: A case-control study of 281 HFMD patients from the First People's Hospital of Pingdingshan in Pingdingshan city, Henan province, central China, and 222 controls from Pingdingshan city was conducted. Anti-T. gondii antibodies were serologically detected using the enzyme-linked immunosorbent assay. Results: We found that the overall anti-T. gondii immunoglobulin G (IgG) antibody prevalence among HFMD patients was 12.46%, which was significantly higher than that in clinically healthy children (1.80%). The highest T. gondii seroprevalence was detected in critical cases (22.58%), followed by severe cases (11.50%), and the lowest was detected in mild cases (8.33%). Conclusion: The present study is the first survey of T. gondii seroprevalence among HFMD patients in China; 12.46% were defined as seropositive. It is imperative that improved integrated measures are taken to prevent and control T. gondii infection among HFMD patients. [ABSTRACT FROM AUTHOR]

TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family that participates in HIV-1 pathogenesis through the depletion of CD4+ T cells. TRAIL is expressed on the cell membrane of peripheral immune cells and can be cleaved into a soluble, secreted form. The regulation of TRAIL in macrophages during HIV-1 infection is not completely understood. In this study, we investigated the mechanism(s) of TRAIL expression in HIV-1-infected macrophages, an important cell type in HIV-1 pathogenesis. A human monocyte-derived macrophage (MDM) culture system was infected with macrophage-tropic HIV-1ADA, HIV-1JR-FL, or HIV-1BAL strains. TRAIL, predominantly the membrane-bound form, increased following HIV-1 infection. We found that HIV-1 infection also induced interferon regulatory factor (IRF)-1, IRF-7 gene expression and signal transducers and activators of transcription 1 (STAT1) activation. Small interfering RNA knockdown of IRF-1 or IRF-7, but not IRF-3, reduced STAT1 activation and TRAIL expression. Furthermore, the upregulation of IRF-1, IRF-7, TRAIL, and the activation of STAT1 by HIV-1 infection was reduced by the treatment of type I interferon (IFN)- neutralizing antibodies. In addition, inhibition of STAT1 by fludarabine abolished IRF-1, IRF-7, and TRAIL upregulation. We conclude that IRF-1, IRF-7, type I IFNs, and STAT1 form a signaling feedback loop that is critical in regulating TRAIL expression in HIV-1-infected macrophages. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) latency has been associated with a variety of human cancers. Latent membrane protein 1 (LMP-1) is one of the key viral proteins required for transformation of primary B cells in vitro and establishment of EBV latency. We have previously shown that LMP-1 induces the expression of several interferon (IFN)-stimulated genes and has antiviral effect (Zhang, J., Das, S. C., Kotalik, C., Pattnaik, A. K., and Zhang, L. (2004) J. Biol. Chem. 279, 46335–46342), in this report, a novel mechanism related to the antiviral effect of LMP-1 is identified. We show that EBV type III latency cells, in which LMP-1 is expressed, are primed to produce robust levels of endogenous IFNs upon infection of Sendai virus. The priming action is due to the expression of LMP-1 but not EBV nuclear antigen 2 (EBNA-2). The signaling events from the C-terminal activator regions of LMP-1 are essential to prime cells for high IFN production. LMP-l-mediated activation of NF-κB is apparently necessary and sufficient for LMP-1-mediated priming effect in DG75 cells, a human B cell line. IFN regulatory factor 7 (IRF-7) that can be activated by LMP-1 is also implicated in the priming action. Taken together, these data strongly suggest that LMP-1 may prime EBV latency cells for IFN production and that the antiviral property of LMP-1 may be an intrinsic part of EBV latency program, which may assist the establishment and/or maintenance of viral latency. [ABSTRACT FROM AUTHOR]

Human herpesvirus 8 (HHV-8)/Kaposi's sarcoma-associated herpesvirus infection goes through lytic and latent phases that are regulated by viral gene products, but very little is known about the involvement of host proteins. The replication and transcription activator (RTA) is a viral protein sufficient to initiate lytic replication by activating downstream genes, including the viral early gene open reading frame 57 (ORF 57), which codes for a posttranscriptional activator. In this study, we demonstrate that cellular interferon regulatory factor 7 (IRF-7) negatively regulates this process by competing with RTA for binding to the RTA response element in the ORF 57 promoter to down-regulate RTA-induced gene expression. We also show that alpha interferon represses RTA-mediated transactivation and that repression involves IRF-7. Our study indicates that upon HHV-8 infection, the host responds by suppression of lytic gene expression through binding of IRF-7 to the lytic viral gene promoter. These findings suggest that HHV.8 has developed a novel mechanism to induce but then subvert the innate antiviral response, specifically the interferon-signaling pathway, to regulate RTA activity and ultimately the viral latent/lytic replicative cycle. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) is a neurotropic flavivirus that causes several diseases including birth defects such as microcephaly. Intrinsic immunity is known to be a frontline defense against viruses through host anti-viral restriction factors. Limited knowledge is available on intrinsic immunity against ZIKV in brains. Amyloid precursor protein (APP) is predominantly expressed in brains and implicated in the pathogenesis of Alzheimer's diseases. We have found that ZIKV interacts with APP, and viral infection increases APP expression via enhancing protein stability. Moreover, we identified the viral peptide, HGSQHSGMIVNDTGHETDENRAKVEITPNSPRAEATLGGFGSLGL, which is capable of enhancing APP expression. We observed that aging brain tissues with APP had protective effects on ZIKV infection by reducing the availability of the viruses. Also, knockdown of APP expression or blocking ZIKV-APP interactions enhanced ZIKV replication in human neural progenitor/stem cells. Finally, intracranial infection of ZIKV in APP-null neonatalmice resulted in highermortality and viral yields. Taken together, these findings suggest that APP is a restriction factor that protects against ZIKV by serving as a decoy receptor, and plays a protective role in ZIKV-mediated brain injuries. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is associated with multiple human malignancies. EBV latent membrane protein 1 (LMP1) is required for the efficient transformation of primary B lymphocytes in vitro and possibly in vivo. The tumor suppressor p53 plays a seminal role in cancer development. In some EBV-associated cancers, p53 tends to be wild type and overly expressed; however, the effects of p53 on LMP1 expression is not clear. We find LMP1 expression to be associated with p53 expression in EBVtransformed cells under physiological and DNA damaging conditions. DNA damage stimulates LMP1 expression, and p53 is required for the stimulation. Ectopic p53 stimulates endogenous LMP1 expression. Moreover, endogenous LMP1 blocks DNA damage-mediated apoptosis. Regarding the mechanism of p53-mediated LMP1 expression, we find that interferon regulatory factor 5 (IRF5), a direct target of p53, is associated with both p53 and LMP1. IRF5 binds to and activates a LMP1 promoter reporter construct. Ectopic IRF5 increases the expression of LMP1, while knockdown of IRF5 leads to reduction of LMP1. Furthermore, LMP1 blocks IRF5-mediated apoptosis in EBV-infected cells. All of the data suggest that cellular p53 stimulates viral LMP1 expression, and IRF5 may be one of the factors for p53-mediated LMP1 stimulation. LMP1 may subsequently block DNA damage- and IRF5-mediated apoptosis for the benefits of EBV. The mutual regulation between p53 and LMP1 may play an important role in EBV infection and latency and its related cancers. [ABSTRACT FROM AUTHOR]

Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is a human gammaherpesvirus associated with several human malignancies. The replication and transcription activator (RTA) is necessary and sufficient for the switch from KSHV latency to lytic replication. Interleukin 1 (IL-1) is a major mediator for inflammation and plays an important role in both innate and adaptive immunity. Myeloid differentiation primary response gene 88 (MyD88) is an essential adaptor molecule for IL-1 as well as most Toll-like receptor signaling. In this study, we identified a novel mechanism by which KSHV interferes with host inflammation and immunity. KSHV RTA specifically reduces the steady-state protein levels of MyD88, and physiological levels of MyD88 are downregulated during KSHV lytic replication when RTA is expressed. The N-terminal region of RTA is required for the reduction of MyD88. Additional studies demonstrated that RTA targets MyD88 expression at the RNA level, inhibits RNA synthesis of MyD88, and may bind MyD88 RNA. Finally, RTA inhibits IL-1-mediated activation of NF-κB. Because IL-1 is abundant in the KS microenvironment and inhibits KSHV replication, this work may expand our understanding of how KSHV evades host inflammation and immunity for its survival in vivo. [ABSTRACT FROM AUTHOR]

Objective: Reform of the health care system in urban areas of China has prompted concerns about the utilization of Community Health Centers (CHC). This study examined which of the dominant primary care delivery models, i.e., the public CHC model, the 'gate-keeper' CHC model, or the hospital-owned CHC models, was most effective in enhancing access to and quality of care for patients with chronic illness. Methods: The case-comparison design was used to study nine health care organizations in Guangzhou, Dongguan, and Shenzhen cities within Guangdong province, China. 560 patients aged 50 or over with hypertension or diabetes who visited either CHCs or hospitals in these three cities were surveyed by using face-to-face interviews. Bivariate analyses were performed to compare quality and value of care indicators among subjects from the three cities. Multivariate analyses were used to assess the association between type of primary care delivery and quality as well as value of chronic care after controlling for patients' demographic and health status characteristics. Results: Patients from all three cities chose their current health care providers primarily out of concern for quality of care (both provider expertise and adequate medical equipment), patient-centered care, and insurance plan requirement. Compared with patients from Guangzhou, those from Dongguan performed significantly better on most quality and value of care indicators. Most of these indicators remained significantly better even after controlling for patients' demographic and health status characteristics. The Shenzhen model (hospital-owned and -managed CHC) was generally effective in enhancing accessibility and continuity. However, coordination suffered due to seemingly duplicating primary care outpatients at the hospital setting. Significant associations between types of health care facilities and quality of care were also observed such that patients from CHCs were more likely to be satisfied with traveling time and follow-up care by their providers. Conclusion: The study suggested that the Dongguan model (based on insurance mandate and using family practice physicians as 'gate-keepers') seemed to work best in terms of improving access and quality for patients with chronic conditions. The study suggested adequately funded and well-organized primary care system can play a gatekeeping role and has the potential to provide a reasonable level of care to patients. [ABSTRACT FROM AUTHOR]

Kaposi's sarcoma-associated herpesvirus (KSHV) is a human γ-herpesvirus. KSHV replication and transcription activator (RTA) is necessary and sufficient for KSHV reactivation from latency. Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns, act through adaptors, and initiate innate and adaptive immune responses against pathogens. Toll/interleukin-1- receptor domain containing adaptor protein inducing interferon- α (TRIF) is an adaptor associated with TLR3 and TLR4 signaling, and is closely related to antiviral signaling to activate type I interferon (IFN) production. We previously found that KSHVRTA degrades TRIF indirectly and blocks TLR3 pathways. In this report, we find that TRIF, as well as TLR3 activation, enhances KSHVRTA protein expression. The C-terminal region of the RTA is involved in the responding TRIF-mediated enhancement. The degradation of TRIF and the enhancement of RTA expression are using two different pathways. The enhancement by TLR-TRIF is at least partially via promoting translational efficiency of RTA mRNA. Finally, the receptor-interacting protein 1 (RIP1) may be involved in TRIF mediated enhancement of RTA expression, but not in the RTA mediated degradation of TRIF. Therefore, the activation of TLRTRIF pathway enhances KSHV RTA protein expression, and KSHV RTA in turn degrades TRIF to block innate immunity. The putative KSHV-TLR-adaptor-interacting loop may be a critical element to evade and usurp host innate immunity in KSHV life-cycle. [ABSTRACT FROM AUTHOR]

JC virus, JCV, is a human neurotropic polyomavirus whose replication in glial cells causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). In addition, JCV possesses oncogenic activity and expression of its transforming protein, large T-antigen (T-Ag), in several experimental animals induces tumors of neural origin. Further, the presence of JCV DNA and T-Ag have been repeatedly observed in several human malignant tissues including primitive neuroectodermal tumors and glioblastomas. Earlier studies have demonstrated that Bag3, a member of the Bcl-2-associated athanogene (Bag) family of proteins, which is implicated in autophagy and apoptosis, is downregulated upon JCV infection of glial cells and that JCV T-Ag is responsible for suppressing the activity of the BAG3 promoter. Here, we investigated the possible impact of Bag3 on T-Ag expression in JCV-infected human primary glial cells as well as in cells derived from T-Ag- induced medulloblastoma in transgenic animals. Results from these studies revealed that overexpression of Bag3 drastically decreases the level of T-Ag expression by inducing the autophagic degradation of the viral protein. Interestingly, this event leads to the inhibition of JCV infection of glial cells, suggesting that the reduced levels of T-antigen seen upon the overexpression of Bag3 has a biological impact on the viral lytic cycle. Results from protein-protein interaction studies showed that T-Ag and Bag3 physically interact with each other through the zinc-finger of T-Ag and the proline rich domains of Bag3, and this interaction is important for the autophagic degradation of T-Ag. Our observations open a new avenue of research for better understanding of virus-host interaction by investigating the interplay between T-Ag and Bag3, and their impact on the development of JCV-associated diseases. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus. Toll-like receptor 7 (TLR7) is involved in host innate immunity against pathogens, and its aberrant activation is linked to the development of systemic lupus erythematosus (SLE, also called "lupus"). Type I interferons (IFN) are apparently driving forces for lupus pathogenesis. Previously, we found that EBV latent membrane protein 1 (LMP1) primes cells for IFN production. In this report, the relationship among EBV LMP1, TLRs, and IFN production are examined. We find that TLR7 activation increases the expression of EBV LMP1, and IFN regulatory factor 7 (IRF7) is involved in the stimulation process. TLR7 activation did not induce IFNs from EBV-infected cells, but potentiates those cells for IFN production by TLR3 or TLR9 activation. In addition, we find that LMP1 and IFNs are co- expressed in the same cells in some lupus patients. Therefore, the aberrant activation of TLR7 might induce LMP1 expression and LMP1-expression cells may be producing IFNs in lupus patients. These results suggest EBV might be an exacerbating factor in some lupus patients via promoting IFN production. [ABSTRACT FROM AUTHOR]

The cellular interferon regulatory factor-4 (IRF-4), which is a member of IRF family, is involved in the development of multiple myeloma and Epstein-Barr virus (EBV)-mediated transformation of B lymphocytes. However, the molecular mechanism of IRF-4 in cellular transformation is unknown. We have found that knockdown of IRF-4 leads to high expression of IRF-5, a pro-apoptotic member in the IRF family. Overexpression of IRF-4 represses IRF-5 expression. Reduction of IRF-4 leads to growth inhibition, and the restoration of IRF-4 by exogenous plasmids correlates with the growth recovery and reduces IRF-5 expression. In addition, IRF-4 negatively regulates IRF-5 promoter reporter activities and binds to IRF-5 promoters in vivo and in vitro. Knockdown of IRF-5 rescues IRF-4 knockdown-mediated growth inhibition, and IRF-5 overexpression alone is sufficient to induce cellular growth inhibition of EBV-transformed cells. Therefore, IRF-5 is one of the targets of IRF-4, and IRF-4 regulates the growth of EBV-transformed cells partially through IRF-5. This work provides insight on how IRFs interact with one another to participate in viral pathogenesis and transformation. [ABSTRACT FROM AUTHOR]

Kaposi sarcoma-associated herpesvirus (KSHV) is a human γ-herpesvirus associated with several human malignancies. The replication and transcription activator (RTA) is necessary and sufficient for the switch from KSHV latency to lytic replication. Toll-interleukin-1 receptor (TIR) domain-containing adaptor-inducing β-interferon (TRIF, also called TIR-domain-containing adaptor molecule-1 (TICAM-1)) is a signaling adaptor molecule that is critically involved in the Toll-like receptor 3 (TLR-3) and TLR-4 signaling pathways for type I interferon (IFN) production, a key component of innate immunity against microbial infection. In this report, we find a new mechanism by which RTA blocks innate immunity by targeting cellular TRIF. RTA specifically degrades TRIF by shortening the half-life of TRIF protein. This RTA-mediated degradation is at least partially mediated through the ubiquitin-proteasome pathway because proteasome inhibitors as well as knockdown of cellular ubiquitin expression alleviate the degradation. RTA may not directly interact with TRIF and may activate TRIF degradation indirectly through an unknown mediator(s). RTA targets multiple regions of TRIF and may use its ubiquitin ligase domain for the degradation. In addition, physiological levels of TRIF protein are down-regulated during KSHV lytic replication when RTA is expressed. Finally, RTA down-regulates double-stranded RNA-initiated activation of TLR-3 pathway, in the absence of degradation of IFN regulatory factor 7 (IRF-7). Taken together, these data suggest that KSHV employs a novel mechanism to block the innate immunity by degrading TRIF protein. This work may contribute to our understandings on how KSHV evades host immunity for its survival in vivo. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) infection is associated with several human malignancies. Interferon (IFN) regulatory factor 7 (IRF-7) has several splicing variants, and at least the major splicing variant (IRF-7A) has oncogenic potential and is associated with EBV transformation processes. IRF-7C is an alternative splicing variant with only the DNA-binding domain of IRF-7. Whether IRF-7C is present under physiological conditions and its functions in viral transformation are unknown. In this report, we prove the existence of IRF-7C protein and RNA in certain cells under physiological conditions, and find that high levels of IRF-7C are associated with EBV transformation of human primary B cells in vitro as well as EBV type III latency. EBV latent membrane protein 1 (LMP-1) stimulates IRF-7C expression in B lymphocytes. IRF-7C has oncogenic potential in rodent cells and partially restores the growth properties of EBV-transformed cells under a growth-inhibition condition. A tumor array experiment has identified six primary tumor specimens with high levels of IRF-7C protein—all of them are lymphomas. Furthermore, we show that the expression of IRF-7C is apparently closely associated with other IRF-7 splicing variants. IRF-7C inhibits the function of IRF-7 in transcriptional regulation of IFN genes. These data suggest that EBV may use splicing variants of IRF-7 for its transformation process in two strategies: to use oncogenic properties of various IRF-7 splicing variants, but use one of its splicing variants (IRF-7C) to block the IFN-induction function of IRF-7 that is detrimental for viral transformation. The work provides a novel relation of host/virus interactions, and has expanded our knowledge about IRFs in EBV transformation. [ABSTRACT FROM AUTHOR]

Background: Both Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are members of the human gamma herpesvirus family: each is associated with various human cancers. The majority of AIDS-associated primary effusion lymphoma (PEL) are co-infected with both KSHV and EBV. Dually-infected PELs selectively switch from latency to lytic replication of either KSHV or EBV in response to chemical stimuli. KSHV replication and transcription activator (K-RTA) is necessary and sufficient for the switch from KSHV latency to lytic replication, while EBV BZLF1 gene product (EBV-Z) is a critical initiator for induction of EBV lytic replication. Methodology/Principal Findings: We show K-RTA and EBV-Z are co-localized and physically interact with each other in dually-infected PELs. K-RTA inhibits the EBV lytic replication by nullifying EBV-Z-mediated EBV lytic gene activation. EBV-Z inhibits KSHV lytic gene expression by blocking K-RTA-mediated transactivations. The physical interaction between K-RTA and EBV-Z are required for the mutual inhibition of the two molecules. The leucine heptapeptide repeat (LR) region in K-RTA and leucine zipper region in EBV-Z are involved in the physical interactions of the two molecules. Finally, initiation of KSHV lytic gene expression is correlated with the reduction of EBV lytic gene expression in the same PEL cells. Conclusions/Significance: In this report, how the two viruses interact with each other in dually infected PELs is addressed. Our data may provide a possible mechanism for maintaining viral latency and for selective lytic replication in dually infected PELs, i.e., through mutual inhibition of two critical lytic replication initiators. Our data about putative interactions between EBV and KSHV would be applicable to the majority of AIDS-associated PELs and may be relevant to the pathogenesis of PELs. [ABSTRACT FROM AUTHOR]

Background: Comparative genomics has become an essential approach for identifying homologous gene candidates and their functions, and for studying genome evolution. There are many tools available for genome comparisons. Unfortunately, most of them are not applicable for the identification of unique genes and the inference of phylogenetic relationships in a given set of genomes. Results: GenomeBlast is a Web tool developed for comparative analysis of multiple small genomes. A new parameter called "coverage" was introduced and used along with sequence identity to evaluate global similarity between genes. With GenomeBlast, the following results can be obtained: (1) unique genes in each genome; (2) homologous gene candidates among compared genomes; (3) 2D plots of homologous gene candidates along the all pairwise genome comparisons; and (4) a table of gene presence/absence information and a genome phylogeny. We demonstrated the functions in GenomeBlast with an example of multiple herpesviral genome analysis and illustrated how GenomeBlast is useful for small genome comparison. Conclusion: We developed a Web tool for comparative analysis of small genomes, which allows the user not only to identify unique genes and homologous gene candidates among multiple genomes, but also to view their graphical distributions on genomes, and to reconstruct genome phylogeny. GenomeBlast runs on a Linux server with 4 CPUs and 4 GB memory. [ABSTRACT FROM AUTHOR]

Kaposi's sarcoma-associated herpesvirus (also called human herpesvirus 8 [HHV-8]) replication and transcription activator (RTA) is apparently necessary and sufficient for the switch from viral latency to lytic replication. RTA may regulate open reading frame (ORF) K14 (viral OX-2 homologue) and ORF74 (viral G-protein-coupled receptor homologue) genes through an interferon-stimulated response element (ISRE)-like sequence (K14 ISRE) in the promoter region. RTA strongly activated a K14 ISRE-containing K14-ORF74 promoter reporter construct and a heterologous promoter reporter construct containing K14 ISRE. RTA could bind to K14 ISRE and other ISREs, activate promoter reporter constructs from interferon-simulated genes (ISGs), and selectively induce three endogenous ISGs in primary endothelial cells: ISG-54, myxovirus resistance protein 1 (MxA), and stimulated trans-acting factor of 50 kDa. In addition, a region in the RTA DNA-binding domain has been identified with certain sequence similarity to the DNA-binding domains of the interferon regulatory factor (IRF) family. Mutation in one conserved amino acid within this region reduced the ability of RTA to bind to ISRE as well as other RTA response elements. Furthermore, the mutant failed to activate RTA-responsive promoters and to induce viral lytic gene expression. The mutation at the same conserved amino acid residue in IRF-7 drastically reduced its ability to bind to DNA and to activate the beta interferon promoter. The sequence and functional similarities between RTA and IRFs suggest that the HHV-8 RTA may usurp the cellular IRF pathway. [ABSTRACT FROM AUTHOR]

The majority of AIDS-associated primary effusion lymphomas (PEL) are latently infected with both Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). PELs harboring two viruses have higher oncogenic potential, suggesting functional interactions between EBV and KSHV. The KSHV replication and transcription activator (K-RTA) is necessary and sufficient for induction of KSHV lytic replication. EBV latent membrane protein 1 (LMP-1) is essential for EBV transformation and establishment of latency in vitro. We show EBV inhibits chemically induced KSHV lytic replication, in part because of a regulatory loop in which K-RTA induces EBV LMP-1 and LMP-1 in turn inhibits K-RTA expression and furthermore the lytic gene expression of KSHV. Suppression of LMP-1 expression in dually infected PEL cells enhances the expression of K-RTA and lytic replication of KSHV upon chemical induction. Because LMP-1 is known to inhibit EBV lytic replication, KSHV-mediated induction of LMP-1 would potentiate EBV latency. Moreover, KSHV infection of EBV latency cells induces LMP-1, and K-RTA is involved in the induction. Both LMP-1 and K-RTA are expressed during primary infection by EBV of KSHV latency cells. Our findings provide evidence that an interaction between EBV and KSHV at molecular levels promotes the maintenance and possibly establishment of viral latency, which may contribute to pathogenesis of PELs. [ABSTRACT FROM AUTHOR]