A comparative review of HLA associations with hepatitis Band C viral infections across global populations

Hepatitis B （HBV） and hepatitis C （HCV） viral infection or co-infection leads to risk of development of chronic infection, cirrhosis and hepatocellular carcinoma （HCC）. Immigration and globalization have added to the challenges of public health concerns regarding chronic HBV and HCV infections worldwide. The aim of this study is to review existing global literature across ethnic populations on HBV and HCV related human leukocyte antigen （HLA） associations in relation to susceptibility, viral persistence and treatment. Extensive literature search was conducted to explore the HLA associations in HBV and HCV infections reported across global populations over the past decade to understand the knowledge status, weaknesses and strengths of this information in different ethnic populations. HLA DR13 is consistently associated with HBV clearance globally. HLADRB1＊11/＊12 alleles and DQB1＊0301 are associated with HBV persistence but with HCV clearance worldwide. Consistent association of DRB1＊03 and ＊07 is observed with HCV susceptibility and non-responsiveness to HBV vaccination across the population. HLA DR13 is protective for vertical HBV and HCV transmission in Chinese and Italian neonates, but different alleles are associated with their susceptibility in these populations. HLA class I molecule interactions with Killer cell immunoglobulin like receptors （KIR） of natural killer （NK） cells modulate HCV infection outcome via regulating immune regulatory cells and molecules. HLA associations with HBV vaccination, interferon therapy in HBV and HCV, and with extra hepatic manifestations of viral hepatitis are also discussed. Systematic studies in compliance with global regulatory standards are required to identify the HLA specific viral epitope, stage specific T cell populations interacting with different HLA alleles during disease progression and viral clearance of chronic HBV or HCV infections among different ethnic populations. These studies would facilitate stage specific therapeutic strategies for clearance of HBV and HCV infections or co-infections across global populations and aid in identification of HBV-HCV combined vaccine. HLA associations of chronic HBV or HCV development with confounding host factors including alcohol, drug abuse, insulin resistance, age and gender are lacking and warrant detailed investigation across global populations.

Management of hepatitis C virus infection in HIV/HCV co-infected patients: Clinical review

Nearly one fourth of individuals with human immunodeficiency virus (HIV) infection have hepatitis C virus (HCV) infection in the US and Western Europe. With the availability of highly active antiretroviral therapy and the consequent reduction in opportunistic infections, resulting in the prolongation of the life span of HIV-infected patients, HCV co-infection has emerged as a signif icant factor influencing the survival of HIV patients. Patients with HIV/HCV co-infection have a faster rate of fibrosis progression resulting in more frequent occurrences of cirrhosis, end-stage liver disease, and hepatocellular carcinoma. However, the mechanism of interaction between the two viruses is not completely understood. The treatment for HCV in co-infected patients is similar to that of HCV monoinfection; i.e., a combination of pegylated interferon and ribavirin. The presence of any barriers to antiHCV therapy should be identified and eliminated in order to recruit all eligible patients. The response to treatment in co-infected patients is inferior compared to the response in patients with HCV mono-infection. The sustained virologic response rate is only 38% for genotype-1 and 75% for genotype-2 and -3 infections. Liver transplantation is no longer considered a contraindication for end-stage liver disease in coinfected patients. However, the 5 year survival rate is lower in co-infected patients compared to patients with HCV mono-infection (33% vs 72%, P = 0.07). A better understanding of liver disease in co-infected patients is needed to derive new strategies for improving outcome and survival.

Hepatitis B virus and hepatocellular carcinoma at the miRNA level

AIM: To study Hepatitis B virus (HBV) infection and its association with hepatocellular carcinoma (HCC) at the miRNA level.METHODS: Three cellular models were used to investigate miRNA expression changes during HBV infection: human HepG2 hepatoblastoma cell line as a model without HBV infection;HepG2 cell line transfected with a 1.3-fold full-length HBV genome as an acute infection model;and HepG2.2.15 cell line,which is derived from HepG2 and stably transfected with a complete HBV genome,as a chronic infection model.The miRNA levels were examined using microarray technology.To explore the relationship between HBV infection and HCC genesis at the miRNA level,we downloaded from national center for biotechnology information Gene Expression Omnibus an miRNA expression dataset derived from HCC patients,most of whom are HBV carriers.We compared the miRNA expression alterations during HBV infection with those in HCC patients,by analyzing miRNA expression change profiles statistically.RESULTS: Seventy-seven and 48 miRNAs were differentially expressed during acute and chronic HBV infection,respectively.Among these miRNAs,25 were in common,the intersection of which was significant under the hypergeometric test (P = 1.3 × 10-11).Fourteen miRNAs were observed to change coherently in the acute and chronic infections,with one upregulated and 13 downregulated.Eleven showed inverse changes during the two phases of infection;downregulated in the acute infection and upregulated in the chronic infection.The results imply that common and specific mechanisms exist at the miRNA level during acute and chronic HBV infection.Besides,comparative analysis of the miRNA expression changes during HBV infection with those in HCC indicates that,although miRNA expression changes during HBV infection are distinct from those in HCC patients (P < 2.2 × 10-16),they exhibited significant correlations (P = 0.0229 for acute infection;P = 0.0084 for chronic infection).Perturbation of miRNA expression during chronic HBV infection was closer to that in HCC patients than that during acute HBV infection.This observation implies the contribution of miRNAs to HCC genesis from HBV infection.According to their patterns of differential expression in acute and chronic HBV infection,as well as in HCC,miRNAs of potential research interest could be identified,such as miR-18a/miR-18b,miR-106a,miR-221 and miR-101.For instance,the gradient expression alteration of miR-221 in the above three phases,which is downregulated in acute HBV infection,normally expressed in chronic HBV infection,and upregulated in HCC,indicates that it may be a key effector for progression of the disease.CONCLUSION: Our analysis provides insights into HBV infection and related HCC in relation to miRNAs,and reveals some candidate miRNAs for future studies.

An Overview of the Highly Pathogenic H5N1 Influenza Virus

Since the first human case of H5N1 avian influenza virus infection was reported in 1997, this highly pathogenic virus has infected hundreds of people around the world and resulted in many deaths. The ability of H5N1 to cross species boundaries, and the presence of polymorphisms that enhance virulence, present challenges to developing clear strategies to prevent the pandemic spread of this highly pathogenic avian influenza (HPAI) virus. This review summarizes the current understanding of, and recent research on, the avian influenza H5N1 virus, including transmission, virulence, pathogenesis, clinical characteristics, treatment and prevention.

The host type I interferon response to viral and bacterial infections

Type I interferons (IFN) are well studied cytokines with anti-viral and immune-modulating functions. Type I IFNsare produced following viral infections, but until recently, the mechanisms of viral recognition leading to IFN productionwere largely unknown. Toll like receptors (TLRs) have emerged as key transducers of type I IFN during viral infectionsby recognizing various viral components. Furthermore, much progress has been made in defining the signaling path-ways downstream of TLRs for type I IFN production. TLR7 and TLR9 have become apparent as universally importantin inducing type I IFN during infection with most viruses, particularly by plasmacytoid dendritic cells. New intracellularviral pattern recognition receptors leading to type I IFN production have been identified. Many bacteria can also inducethe up-regulation of these cytokines. Interestingly, recent studies have found a detrimental effect on host cells if type IIFN is produced during infection with the intracellular gram-positive bacterial pathogen, Listeria monocytogenes. Thisreview will discuss the recent advances made in defining the signaling pathways leading to type I IFN production.

Respiratory Virus Multiplex RT-PCR Assay Sensitivities and Influence Factors in Hospitalized Children with Lower Respiratory Tract Infections

Multiplex RT-PCR assays have been widely used tools for detection and differentiation of a panel of respiratory viral pathogens. In this study, we evaluated the Qiagen ResPlex lI V2.0 kit and explored factors influencing its sensitivity. Nasopharyngeal swab （NPS） specimens were prospectively collected from pediatric inpatients with lower respiratory tract infections at the time of admission in the Shenzhen Children＇s Hospital from May 2009 to April 2010. Total nucleic acids were extracted using the EZ1 system （Qiagen, Germany） and 17 respiratory viruses and genotypes including influenza A virus （FluA）, FluB, parainfluenza virus 1 （PIV1）, PIV2, PIV3, PIV4, respiratory syncytial virus （RSV）, human metapneumovirus （hMPV）, rhinoviruses （RhV）, enteroviruses （EnV）, human bocaviruses （hBoV）, adenoviruses （AdV）, four coronaviruses （229E, OC43, NL63 and HKU1）, and FluA 2009 pandemic H1NI（H1NI-p） were detected and identified by the ResPlex II kit. In parallel, 16 real-time TaqMan quantitative RT-PCR assays were used to quantitatively detect each virus except for RhV. Influenza and parainfluenza viral cultures were also performed. Among the total 438 NPS specimens collected during the study period, one or more viral pathogens were detected in 274 （62.6%） and 201（45.9%） specimens by monoplex TaqMan RT-PCR and multiplex ResPlex, respectively. When results from monoplex PCR or cell culture were used as the reference standard, the multiplex PCR possessed specificities of 92.9-100.0%. The sensitivity of multiplex PCR for PIV3, hMPV, PIV1 and BoV were 73.1%, 70%, 66.7% and 55.6%, respectively, while low sensitivities （11.1%-40.0%） were observed for FluA, EnV, OC43, RSV and H1N1. Among the seven viruses/genotypes detected with higher frequencies, multiplex PCR sensitivities were correlated significantly with viral loads determined by the TaqMan RT-PCR in FluA, H 1N 1-p and RSV （p=0.011-0.000） The Qiagen ResPlex II multiplex RT-PCR kit possesses excellent specificity for simultaneous detection of 17 viral pathogens in NPS specimens in pediatric inpatients at the time of admission. The sensitivity of multiplex RT-PCR was influenced by viral loads, specimen process methods, primer and probe design and amplification condition.

Prevalence and risk factors of asymptomatic hepatitis C virus infection in Egyptian children

AIM: To identify the prevalence, risk factors and manifestations of asymptomatic hepatitis C virus (HCV) infection in Egyptian children. METHODS: Children at the age of 1-9 years were screened for HCV antibodies and alanine aminotransferase (ALT) levels. Every child with elevated ALT and/or detectable HCV antibodies was tested for HCV RNA by RT-PCR and compared with two negative controls for risk factors and signs and symptoms of liver disease.RESULTS: We screened 1042 children, six of them had elevated ALT, negative HCV antibody and positive RNA, likely representing acute hepatitis C cases. Fifteen children were HCV seropositive, 5 of them were HCV RNA positive. Asymptomatic HCV infection was present in 2.02% (positive results for either HCV antibodies or HCV-RNA or both). Symptoms such as diarrhea, abdominal pain, history of fatigue and school absence because of illness and risk factors such as dental care were significantly more common among HCV positive cases than among controls. None of the HCV positive children was diagnosed as having signs of advanced liver disease upon clinical or ultrasonographic examination. CONCLUSION: Asymptomatic HCV infection is detectable in 2.02% Egyptian children.

Impact of human immunodeficiency virus infection on the course of hepatitis C virus infection: A meta-analysis

AIM: To analyze the influence of human immunodeficiency virus (HIV) infection on the course of hepatitis C virus (HCV) infection. METHODS: We performed a meta-analysis to quantify the effect of HIV co-infection on progressive liver disease in patients with HCV infection. Published studies in the English or Chinese-language medical literature involving cohorts of HIV-negative and -positive patients coinfected with HCV were obtained by searching the PUBMED, EMBASE and CBM. Data were extracted independently from relevant studies by 2 investigators and used in a fixed-effect meta analysis to determine the difference in the course of HCV infection in the 2 groups. RESULTS: Twenty-nine trails involving 16 750 patients were identified including the outcome of histological fibrosis or cirrhosis or de-compensated liver disease or hepatocellular carcinoma or death. These studies yielded a combined adjusted odds ratio (OR) of 3.40 [95% confidence interval (CI) = 2.45 and 4.73]. Of note, studies that examined histological fibrosis/ cirrhosis, decompensated liver disease, hepatocellular carcinoma or death had a pooled OR of 1.47 (95% CI = 1.27 and 1.70), 5.45 (95% CI = 2.54 and 11.71), 0.76 (95% CI = 0.50 and 1.14), and 3.60 (95% CI = 3.12 and 4.15), respectively. CONCLUSION: Without highly active antiretroviral therapies (HAART), HIV accelerates HCV diseaseprogression, including death, histological fibrosis/ cirrhosis and decompensated liver disease. However, the rate of hepatocellular carcinoma is similar in persons who had HCV infection and were positive for HIV or negative for HIV.

SEN virus does not affect treatment response in hepatitis C virus coinfected patients but SEN virus response depends on SEN virus DNA concentration

AIM: To clarify the effect of SEN virus (SENV) infection on a combination therapy including interferon alfa (IFN-α) or pegylated-IFN with ribavirin in patients with chronic hepatitis and the effect of a combination therapy on SENV.METHODS: SENV DNA was determined by polymerase chain reaction in serum samples from 95 patients with chronic hepatitis C. Quantitative analysis was done for SENV H DNA.RESULTS: Twenty-one (22%) of 95 patients were positive for SENV DNA. There was no difference in clinical and biochemical parameters between patients with HCV infection alone and coinfected patients. The sustained response rate for HCV clearance after combination therapy did not differ between patients with SENV (52%) and without SENV(50%, n.s.). SENV DNA was undetectable in 76% of the initially SENV positive patients at the end of follow-up. SENV H response to combination therapy was significantly correlated with SENV DNA level (P=-0.05).CONCLUSION: SENV infection had no influence on the HCV sustained response rate to the combination therapy.Response rate of SENV to the combination therapy depends on SENV DNA level.

Clinical significance of"anti-HBc alone"in human immunodeficiency virus-positive patients

AIM： TO determine the prevalence and clinical relevance of isolated antibodies to hepatitis B core antigen as the only marker of infection （“anti-HBc alone”） among human immunodeficiency virus （HIV） type-1 infected patients. Occult hepatitis B infection frequency was also evaluated. METHODS： Three hundred and forty eight histories from 2388 HIV-positive patients were randomly reviewed. Patients with serological markers of hepatitis B virus （HBV） infection were classified into three groups： past hepatitis, ＂anti-HBc alone＂ and chronic hepatitis. Determination of DNA from HBV, and RNA and genotype from hepatitis C virus （HCV） were performed on ＂anti-HBc alone＂ patients. RESULTS： One hundred and eighty seven （53.7%） HIV-positive patients had markers of HBV infection： 118 past infection （63.1%）, 14 chronic hepatitis （7.5%） and 55 ＂anti-HBc alone＂ （29.4%）. Younger age [2.3-fold higher per every 10 years younger; 95% confidence intervals （Cl） 1.33-4.00] and antibodies to HCV infection [odds ratio （OR） 2.87; 95% CI 1.10-7.48] were factors independently associated with the ＂anti-HBc alone＂ pattern. No differences in liver disease frequency were detected between both groups. Serum levels of anti-HBs were not associated with HCV infection （nor viral replication or HCV genotype）, or with HIV replication or CD4 level. No ＂anti-HBc alone＂ patient tested positive for HBV DNA. CONCLUSION： ＂Anti-HBc alone＂ prevalence in HIM- positive patients was similar to previously reported data and was associated with a younger age and with antibodies to HCV infection. In clinical practice, HBV DNA determination should be performed only in those patients with clinical or analytical signs of liver injury,

Hepatitis C and HIV co-infection:a review

Co-infection with hepatitis C virus and humanimmunodeficiency virus is common in certainpopulations. Among HCV(+) persons, 10 % are alsoHIV (+), and among HIV (+) persons, 25 % are alsoHCV(+). Many studies have shown that in intravenousdrug users, co-infection prevalence can be as high as90-95 %. There is increasing evidence supporting theconcept that people infected with HIV have a muchmore rapid course of their hepatitis C infection.Treatment of co-infection is often challenging becausehighly active anti-retroviral therapy (HAART) therapyis frequently hepatotoxic, especially in the presence ofHCV. The purpose of this review is to describe theeffects that HIV has on hepatitis C, the effects thathepatitis C has on HIV, and the treatment options inthis challenging population.

Occult hepatitis B virus infection:A complex entity with relevant clinical implications

Occult hepatitis B virus(HBV) infection is a world-wide entity,following the geographical distribution of detectable hepatitis B.This entity is defined as the persistence of viral genomes in the liver tissue and in some instances also in the serum,associated to negative HBV surface antigen serology.The molecular basis of the occult infection is related to the life cycle of HBV,which produces a covalently closed circular DNA that persists in the cell nuclei as an episome,and serves as a template for gene transcription.The mechanism responsible for the HBsAg negative status in occult HBV carriers is a strong suppression of viral replication,probably due to the host’s immune response,co-infection with other infectious agents and epigenetic factors.There is emerging evidence of the potential clinical relevance of occult HBV infection,since this could be involved in occult HBV transmission through orthotopic liver transplant and blood transfusion,reactivation of HBV infection during immunosuppression,impairing chronic liver disease outcome and acting as a risk factor for hepatocellular carcinoma.Therefore it is important to bear in mind this entity in cryptogenetic liver diseases,hepatitis C virus/ HIV infected patients and immunosupressed individuals.It is also necessary to increase our knowledge in this fascinating field to define better strategies to diagnose and treat this infection.

The Dicistroviridae: An Emerging Family of Invertebrate Viruses

Dicistroviruses comprise a newly characterized and rapidly expanding family of small RNA viruses of invertebrates. Several features of this virus group have attracted considerable research interest in recent years. In this review I provide an overview of the Dicistroviridae and describe progress made toward the understanding and practical application of dicistroviruses, including (i) construction of the first infectious clone of a dicistrovirus, (ii) use of the baculovirus expression system for production of an infectious dicistrovirus, (iii) the use of Drosophila C virus for analysis of host response to virus infection, and (iv) correlation of the presence of Israeli acute paralysis virus with honey bee colony collapse disorder. The potential use of dicistroviruses for insect pest management is also discussed. The structure, mechanism and practical use of the internal ribosome entry site (IRES) elements has recently been reviewed elsewhere.

Cytomegalovirus enteritis mimicking Crohn's disease in a lupus nephritis patient:A case report

Cytomegalovirus(CMV)infection of the gastrointestinal (GI)tract has been reported in both immunocompetent and,more frequently,in immunocompromised patients.We describe a case of a 19-year-old male who developed CMV infection of the terminal ileum while receiving immunosuppression for lupus nephritis. This was a distinctly unusual site of infection which clinically mimicked Crohn's ileitis.We note that reports of terminal ileal CMV infection have been infrequent. Despite a complicated hospital course,ganciclovir therapy was effective in resolving his symptoms and normalizing his ileal mucosa.This report highlights the importance of accurate histological diagnosis and clinical follow-up of lupus patients with GI symptoms undergoing intense immunosuppression.

Treatment of hepatitis C virus infection

Acute and chronic hepatitis C virus (HCV) infection remains a serious health problem worldwide, however, there has been advancement in the treatment of HCV infection due to standard treatment using pegylated interferon and ribavirin. The literature indicates that therapy for HCV is becoming more individualized. In addition to considering genotype and viral RNA levels before treatment, achievement of an early virologic response (EVR) and a rapid virologic response (RVR) is now possible during therapy. Moreover, problem patients, such as non-responders, relapsers, HIV or HBV co- infected patients, patients with liver cirrhosis, and pre- or post-liver transplantation patients are an increasing fraction of the patients requiring treatment. This article reviews the literature regarding standard treatments and problem patients with acute and chronic HCV infection. It also includes discussion on contraindications and side effects of treatment with interferon and ribavirin, as well as new drug development.

Characterization of a Putative Filovirus Vaccine:Virus-Like Particles

Filoviruses are hemorrhagic fever viruses endemic to parts of Africa and the Philippines. Infection carries with it a mortality rate of up to 90% and currently there are no effective vaccines or therapeutics available to combat infection. However, the filovirus virus-like particles (VLP), which are currently under development, have been shown to be a promising vaccine candidate. They provide protection from infection in the mouse, guinea pig, and nonhuman primate models of infection, eliciting high anti-glycoprotein antibody titers and T cell responses to viral proteins. In this review, we will highlight the development of the filovirus VLP and describe the current understanding of VLP immunogenicity and correlates of protection.

Role of upper endoscopy in diagnosing opportunistic infections in human immunodeficiency virus-infected patients

Highly active antiretroviral therapy (HAART) has dramatically decreased opportunistic infections (OIs) in human immunodef iciency virus (HIV)-infected patients. However,gastrointestinal disease continues to account for a high proportion of presenting symptoms in these patients. Gastrointestinal symptoms in treated patients who respond to therapy are more likely to the result of drug-induced complications than OI. Endoscopic evaluation of the gastrointestinal tract remains a cornerstone of diagnosis,especially in patients with advanced immunodeficiency,who are at risk for OI. The peripheral blood CD4 lymphocyte count helps to predict the risk of an OI,with the highest risk seen in HIV-infected patients with low CD4 count (< 200 cells/mm3). This review provides an update of the role of endoscopy in diagnosing OI in the upper gastrointestinal tract in HIV-infected patients in the era of HAART.

HBVPathDB: A database of HBV infection-related molecular interaction network

AIM: To describe molecules or genes interaction between hepatitis B viruses (HBV) and host, for understanding how virus' and host's genes and molecules are networked to form a biological system and for perceiving mechanism of HBV infection.METHODS: The knowledge of HBV infection-related reactions was organized into various kinds of pathways with carefully drawn graphs in HBVPathDB. Pathway information is stored with relational database management system (DBMS), which is currently the most efficient way to manage large amounts of data and query is implemented with powerful Structured Query Language (SQL). The search engine is written using Personal Home Page (PHP) with SQL embedded and web retrieval interface is developed for searching with Hypertext Markup Language (HTML).RESULTS: We present the first version of HBVPathDB,which is a HBV infection-related molecular interaction network database composed of 306 pathways with 1050molecules involved. With carefully drawn graphs, pathway information stored in HBVPathDB can be browsed in an intuitive way. We develop an easy-to-use interface for flexible accesses to the details of database. Convenient software is implemented to query and browse the pathway information of HBVPathDB. Four search page layout options-category search, gene search, description search,unitized search-are supported by the search engine ofthe database. The database is freely available at http://www.bio-inf, net/HBVPathDB/HBV/.CONCLUSION: The conventional perspective HBVPathDB have already contained a considerable amount of pathway information with HBV infection related, which is suitable for in-depth analysis of molecular interaction network of virus and host. HBVPathDB integrates pathway data-sets with convenient software for query, browsing,visualization, that provides users more opportunity to identify regulatory key molecules as potential drug targets and to explore the possible mechanism of HBV infection based on gene expression datasets.

Expression and its clinical significance of HLA-G in HCMV-infected placenta] villi at early pregnant stage

Objective：To study the expression and its clinical significance of HLA-G in HCMV intrauterine infected placental villi at early pregnant stage. Methods：PCR （polymerase chain reaction） was used to screen the peripheral blood for HCMV-DNA in 462 women who had willingly undergone induced abortion. Then immunohistochemistry was also used to detect expressions of mouse anti-HCMV early antigen （HCMV-EA） and mouse anti-HLA-G in HCMV-DNA positive cases＇ placental villi. The difference of HLA-G expressions between the intrauterine infection group（HCMV-EA positives）, the intrauterine infection-free group（HCMV-EA negatives） and the normal control group （50 cases of healthy early placental villi） was compared. Results： Of the 78 cases, which were detected HCMV-DNA positive, 11 （14.10%） were HCMV-EA positive. Compared with the other two groups, HLA-G expressions in the intrauterine infection group were both obviously decreased（both P〈0. 001）. HLA-G expression positions in all three groups were mainly located in the cytotrophoblast. Conclusion：Intrauterine HCMV infection at early pregnant stage is closely related to HLA-G expression at the maternal-fetal interface. The virogenetic products may affect the expression of HLA-G at the maternal-fetal interface and that of its immunological function, thus leading to different clinical outcomes.