Gene Knockdown in Human Rhinovirus 1B Using 2′-OMe-modified si RNAs Results in the Reactivation of the Interferon Response

The aim of this study was to investigate the knockdown efficiency of 2＇-O-methylated （2＇-OMe）-modified small interfering RNAs （siRNAs） on human rhinovirus 1B （HRV1B） replication and the interferon response. Thus, 24 2＇-OMe-modified siRNAs were designed to target HRV1B. The RNA levels of HRV1B, Toll-like receptor 3, melanoma differentiation-associated gene 5, retinoic acid inducible gene-I, and interferons were determined in HRV1B-infected HeLa and BEAS-2B epithelial cells transfected with 2＇-OMe-modified siRNAs. The results revealed that all 2＇-OMe-modified siRNAs interfered with the replication of HRVIB in a cell-specific and transfection efficiency-dependent manner. Viral activation of Toll-like receptor 3, melanoma differentiation-associated gene 5, retinoic acid inducible gene-1, and the interferon response was detected. In conclusion, the 2＇-OMe-modified siRNAs used in this study could interfere with HRV1B replication, possibly leading to the reactivation of the interferon response.

Alanine aminotransferase normalization at week 8 predicts viral response during hepatitis C treatment

AIM:To investigate alanine aminotransferase(ALT)and sustained virological response(SVR)in chronic hepatitis C(CHC)during peginterferon-ribavirin treatment.METHODS:One hundred and fifty-one genotype 1CHC patients underwent treatment for 48 wk with peginterferon and ribavirin,and were retrospectively divided into two groups as having a rapid virological response(RVR)(Group 1,n=52)and not having an RVR(Group 2,n=99).We also subdivided each group into two according to the initial ALT level being high(Group1h and Group 2h)or normal(Group 1n and Group 2n).HCV RNA and ALT levels were measured at baseline;at 4,12,24 and 48 wk during the treatment period;and at 24 wk follow-up.ALT levels were also obtained at 8 wk.According to the results of ALT,patients were enrolled in either the follow-up abnormal or follow-up normalized ALT groups at each interval.Patients with high and normal ALT levels were compared for each interval in terms of SVR.RESULTS:The SVR rates were 83%vs 40%(P=0.000),82%vs 84%(P=0.830),and 37%vs 44%(P=0.466)when comparing Group 1 with 2,1h with1n,and 2h with 2n,respectively.In Group 2h,the SVR rates were 34%vs 40%(P=0.701),11%vs 52%(P=0.004),12%vs 50%(P=0.007),7%vs 50%(P=0.003),6%vs 53%(P=0.001),and 0%vs 64%(P=0.000)when comparing patients with high and normalized ALT levels at week 4,8,12,24,48 and 72,respectively.The multiple logistic regression analysis revealed that RVR(OR=7.05;95%CI:3.1-16.05,P=0.000),complete early virological response(cEVR)(OR=17.55;95%CI:6.32-48.76,P=0.000),normalization of ALT at8 wk(OR=3.04;95%CI:1.31-7.06,P=0.008),and at 12 wk(OR=4.21;95%CI:1.65-10.76,P=0.002)were identified as independent significant predictive factors for SVR.CONCLUSION:Normalization of ALT at 8 wk may predict viral response during peginterferon-ribavirin treatment in genotype-1 CHC patients especially without RVR.

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.

Heavy smoking and liver

Smoking causes a variety of adverse effects on organs that have no direct contact with the smoke itself such as the liver. It induces three major adverse effects on the liver: direct or indirect toxic effects, immunological effects and oncogenic effects. Smoking yields chemical substances with cytotoxic potential which increase necroinflammation and fibrosis. In addition, smoking increases the production of pro-inflammatory cytokines (IL-1, IL-6 and TNF-α) that would be involved in liver cell injury. It contributes to the development of secondary polycythemia and in turn to increased red cell mass and turnover which might be a contributing factor to secondary iron overload disease promoting oxidative stress of hepatocytes. Increased red cell mass and turnover are associated with increased purine catabolism which promotes excessive production of uric acid. Smoking affects both cell-mediated and humoral immune responses by blocking lymphocyte proliferation and inducing apoptosis of lymphocytes. Smoking also increases serum and hepatic iron which induce oxidative stress and lipid peroxidation that lead to activation of stellate cells and development of fibrosis. Smoking yields chemicals with oncogenic potential that increase the risk of hepatocellular carcinoma (HCC) in patients with viral hepatitis and are independent of viral infection as well. Tobacco smoking has been associated with supression of p53 (tumour suppressor gene). In addition, smoking causes suppression of T-cell responses and is associated with decreased surveillance for tumour cells. Moreover, it has been reported that heavy smoking affects the sustained virological response to interferon (IFN) therapy in hepatitis C patients which can be improved by repeated phlebotomy. Smoker’s syndrome is a clinico-pathological condition where patients complain of episodes of facial flushing, warmth of the palms and soles of feet, throbbing headache, fullness in the head, dizziness, lethargy, prickling sensation, pruritus and arthralgia.

Th1/Th2 type cytokines in hepatitis B patients treated with interferon-α

Objective To investigate the relationship between the expression of Th1/Th2 type cytokines and the effect of interferon-α therapy. Methods Th1/Th2 type cytokines were assayed by enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR) on 23 patients with chronic hepatitis B who were treated with interferon-α.Results Levels of IFN-γ in the supernatant of peripheral blood mononuclear cells (PBMC) cultures from the patients with hepatitis B were slightly lower than those of controls (P=0.07). However, the levels of IL-4 were higher than those of controls (P=0.01). Cytokines measurements during IFN-α treatment showed a trend to decreaseing levels of IL-4 at 4, 12, and 24 weeks. Levels of IFN-γ were slightly increased following IFN-α treatment (P=0.09). In patients with a complete response to IFN-α, the levels of IFN-γ were higher at 24 weeks following IFN-α treatment than that of pre-treatment (P=0.04), and the levels of IL-4 decreased markedly at 12 and 24 weeks (P=0.02, 0.03, respectively). mRNA expression positively correlated with the level of Th1/Th2 type cytokines in the supernatant. Conclusion The expression of Th2 type cytokines is predominant in patients with chronic hepatitis B. Interferon-α therapy can modulate the balance of Th1/Th2 type cytokines, and this is related to its clinical effect. Levels of Th1/Th2 type cytokines could be a predictor of clinical response during Interferon -α treatment.

A molecular arms race between host innate antiviral response and emerging human coronaviruses

Coronaviruses have been closely related with mankind for thousands of years. Communityacquired human coronaviruses have long been recognized to cause common cold. However,zoonotic coronaviruses are now becoming more a global concern with the discovery of highly pathogenic severe acute respiratory syndrome(SARS) and Middle East respiratory syndrome(MERS) coronaviruses causing severe respiratory diseases. Infections by these emerging human coronaviruses are characterized by less robust interferon production. Treatment of patients with recombinant interferon regimen promises beneficial outcomes, suggesting that compromised interferon expression might contribute at least partially to the severity of disease. The mechanisms by which coronaviruses evade host innate antiviral response are under intense investigations. This review focuses on the fierce arms race between host innate antiviral immunity and emerging human coronaviruses. Particularly, the host pathogen recognition receptors and the signal transduction pathways to mount an effective antiviral response against SARS and MERS coronavirus infection are discussed. On the other hand, the counter-measures evolved by SARS and MERS coronaviruses to circumvent host defense are also dissected. With a better understanding of the dynamic interaction between host and coronaviruses, it is hoped that insights on the pathogenesis of newly-identified highly pathogenic human coronaviruses and new strategies in antiviral development can be derived.