Hepatitis: Gu X

Romero V, Azocar J, Zúñiga J, Clavijo OP, Terreros D, Gu X, Husain Z, Chung RT, Amos C, Yunis EJ. · Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA. · Mol Immunol. · Pubmed #18289678 links to  free full text

Abstract: Natural killer cells are important in innate defense against viral infections. The interplay between stimulatory and inhibitory natural killer cell receptors and their corresponding human leukocyte antigen ligands are known to influence the outcome of acute Hepatitis C virus infection. Frequencies of NK receptor genes (8 inhibitory, 6 activating and 2 pseudogenes) and HLA class II alleles (DRB1, DQB1) were analyzed in 160 Puerto-Rican American drug users with Hepatitis C virus infection; 121 had chronic viremia (CV) and 39 were spontaneous clearance (SC). We further ruled out genetic stratification using short tandem repeats. Interaction between KIR gene receptor 2DL3/2DL3 and its ligand, C1/C1 of HLA-Cw alleles and spontaneous clearance was confirmed (p=0.03, OR=3.05). We also found a new interaction between the KIR receptor gene 2DL3 with HLA-DRB1*1201 (p=0.0001, OR=22) associated with SC, and an association of HLA DQB1*0501 (p=0.05, OR=0.30) with CV. Our findings suggested a role for MHC class II alleles in Hepatitis C virus peptide presentation to T cells together with NK ligand interaction involving pathways that will be useful for the development of immunotherapeutic interventions.

Zhu Q, Yu G, Yu H, Lu Q, Gu X, Dong Z, Zhang X. · Department of Infection Diseases, Children's Hospital, Fudan University, Shanghai 200032, China. · Chin Med J (Engl). · Pubmed #12875680 links to  free full text

Abstract: OBJECTIVE: To study the interruptive effect of hepatitis B virus (HBV) specific immunolobulin (HBIG) before delivery in attempt to prevent intrauterine transmission of HBV. METHODS: Nine hundred and eighty HBsAg carrier pregnant women were randomly divided into HBIG group and control group. Each subject in the HBIG group received 200 IU or 400 IU of HBIG intramuscularly at 3, 2 and 1 month before delivery. The subjects in the control group did not receive any specific treatment. All newborn infants received 100 IU of HBIG intramascularly after venous blood samples were taken at birth and 2 weeks after birth, followed by 30 micro g plasma-derived HB vaccine or 5 micro g recombinant yeast-derived hepatitis B vaccine at 1, 2 and 7 months of age. Blood tests were performed for all the lying-in women and their neonates. Blood specimens were tested for HBsAg and HBeAg by enzyme immunoassay. All infants were followed up for 1 year. RESULTS: In the HBIG group, 491 neonates were born to 487 HBV carrier mothers; and in the control group, 496 neonates were born to 493 HBV carrier mothers. The rates of intrauterine transmission in the two groups were 14.3% and 5.7% respectively (chi(2) = 20.280, P < 0.001), and the rates of chronic hepatitis B in the two groups were 2.2% and 7.3% respectively (chi(2) = 13.696, P < 0.001). The high risk factors of intrauterine HBV infection included HBsAg HBeAg double positive and HBV DNA positive in the peripheral blood of pregnant women. CONCLUSION: HBV infection in the uterus may be interrupted by injecting multiple intramuscular HBIG injections before delivery without causing any side-effects.

Lian M, Zhou X, Chen B, Li C, Gu X, Luo M, Zheng X. · National Laboratory of Protein Engineering and Plant Genetic Engineering, Peking University, Beijing, 100871, China. · J Pept Sci. · Pubmed #17918766 No free full text.

Abstract: As a hepatitis B virus (HBV) envelope domain, preS plays significant roles in receptor recognition and viral infection. However, the regions critical for maintaining a stable and functional conformation of preS are still unclear and require further investigation. In order to unravel these regions, serially truncated fragments of preS were constructed and expressed in Escherichia coli. Their solubility, stability, secondary structure, and affinity to polyclonal antibodies and hepatocytes were examined. The results showed that amino acids 31-36 were vital for its stable conformation, and the absence of 10-36 amino acids significantly reduced its binding to polyclonal antibodies as well as hepatocytes. The most stable fragment 1-120 (preS1 + N-terminal 12 amino acids of preS2), perhaps the core of preS, was discovered, which bound to HepG2 cells most tightly. Moreover, the availability of large amounts of well-folded and stable preS1-120 enables us to carry out further structural determination and mechanistic study on HBV infection.

Lian M, Zhou X, Wei L, Qiu S, Zhou T, Li L, Gu X, Luo M, Zheng X. · National Laboratory of Protein Engineering and Plant Genetic Engineering, Peking University, Beijing 100871, China. · Virol J. · Pubmed #17892580 links to  free full text

Abstract: BACKGROUND: Hepatitis B virus (HBV) infection is a serious health problem worldwide. Treatment recommendation and response are mainly indicated by viral load, e antigen (HBeAg) seroconversion, and ALT levels. The S antigen (HBsAg) seroconversion is much less frequent. Since HBeAg can be negative in the presence of high viral replication, preS antigen (HBpreSAg) might be a useful indicator in management of chronic HBV infection. RESULTS: A new assay of double antibody sandwich ELISA was established to detect preS antigens. Sera of 104 HBeAg-negative and 50 HBeAg-positive chronic hepatitis B patients have been studied and 23 HBeAg-positive patients were enrolled in a treatment follow-up study. 70% of the HBeAg-positive patients and 47% of the HBeAg-negative patients showed HBpreSAg positive. Particularly, in the HBeAg-negative patients, 30 out of 47 HBpreSAg positive patients showed no evidence of viral replication based on HBV DNA copies. A comparison with HBV DNA copies demonstrated that the overall accuracy of the HBpreSAg test could reach 72% for active HBV replication. HBpreSAg changes were well correlated with changes of HBsAg, HBV DNA and ALT levels during the course of IFN-alpha treatment and follow-up. HBeAg positive patients responded well to treatment when reduction of HBpreSAg levels was more pronounced. CONCLUSION: Our results suggested that HBpreSAg could be detected effectively, and well correlated with HBsAg and HBV DNA copies. The reduction of HBpreSAg levels in conjunction with the HBV DNA copies appears to be an improved predictor of treatment outcome.

Linton SD, Aja T, Armstrong RA, Bai X, Chen LS, Chen N, Ching B, Contreras P, Diaz JL, Fisher CD, Fritz LC, Gladstone P, Groessl T, Gu X, Herrmann J, Hirakawa BP, Hoglen NC, Jahangiri KG, Kalish VJ, Karanewsky DS, Kodandapani L, Krebs J, McQuiston J, Meduna SP, Nalley K, Robinson ED, Sayers RO, Sebring K, Spada AP, Ternansky RJ, Tomaselli KJ, Ullman BR, Valentino KL, Weeks S, Winn D, Wu JC, Yeo P, Zhang CZ. · Idun Pharmaceuticals, 9380 Judicial Drive, San Diego, CA 92121, USA. · J Med Chem. · Pubmed #16250635 No free full text.

Abstract: A series of oxamyl dipeptides were optimized for pan caspase inhibition, anti-apoptotic cellular activity and in vivo efficacy. This structure-activity relationship study focused on the P4 oxamides and warhead moieties. Primarily on the basis of in vitro data, inhibitors were selected for study in a murine model of alpha-Fas-induced liver injury. IDN-6556 (1) was further profiled in additional in vivo models and pharmacokinetic studies. This first-in-class caspase inhibitor is now the subject of two Phase II clinical trials, evaluating its safety and efficacy for use in liver disease.

Brown LM, Papa RA, Frost MJ, Mackintosh SG, Gu X, Dixon RJ, Shannon AD. · Department of Biological Sciences, University of Western Sydney, Macarthur, P.O. Box 555, Campbelltown, NSW 2560, Australia. · Virus Res. · Pubmed #11900844 No free full text.

Abstract: Truncated NS3 proteins, expressed by recombinant baculoviruses, were used to investigate the location of conserved B-cell epitopes on this non-structural bovine viral diarrhoea virus (BVDV) protein. A goat anti-pestivirus antiserum, and a panel of anti-NS3 monoclonal antibodies, including the BVDV-1 specific antibody P1D8, were used to verify the presence or absence of the epitopes. Interestingly, the monoclonal antibodies reacted only with the truncated protein encompassing the helicase domain of NS3. Expression of the B-cell epitopes was dependent on, but not within, a 57 amino acid sequence at the carboxy-terminal end of this protein, supporting observations that these conserved epitopes are conformational in nature. A comparison of deduced amino acid sequences of the helicase domain from BVDV-1, BVDV-2, BDV and CSFV isolates highlighted a single amino acid that appeared to be unique to P1D8-reactive BVDV-1 isolates. Site-directed mutagenesis studies confirmed that this amino acid is critical for the expression of the BVDV-1 specific NS3 epitope recognised by the P1D8 monoclonal antibody. Surprisingly, the amino acid was also important for an epitope recognised by two group-specific monoclonal antibodies, P1H11 and P4A11. Protein modelling studies, based on the structure of the hepatitis C NS3 helicase domain, indicated that this amino acid occupies a prominent position on the surface of the protein.

Gu X, Li Q, Wang Y. · Infectious Disease Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China. · Zhonghua Gan Zang Bing Za Zhi. · Pubmed #11350683 No free full text.

Abstract: OBJECTIVE: To study the role of bcl-2, bax and hepatocyte apoptosis in the pathogenesis of hepatitis D. METHODS: Expression of HDAg, bcl-2, bax, and hepatocyte apoptosis in liver specimens of 77 patients with hepatitis D were studied by immunohistochemistry, double labelling and serial sections, and TUNEL assay. Six-seven hepatitis B patients served as control. RESULTS: Bcl-2 and bax were mainly expressed in the cytoplasm of hepatocytes, and HDAg mainly in the nucleus of hepatocytes. A large number of HDAg and bax positive cells were distributed among infiltrating lymphocytes at the periportal region in which many apoptosis hepatocytes were found. There were positive correlations between the expression of bax, HDAg and hepatocyte apoptosis (P<0.05). CONCLUSIONS: The distribution and the expression of bax, HDAg and hepatocyte apoptosis are significantly correlated with the activity of inflammation and the severity of the liver damage. Hepatitis D virus infection may induce the expression of bax in the hepatocytes and exacerbate hepatocyte apoptosis through which take a part in the pathogenesis of hepatitis D.

Gu X, Li Q, Wang Y. · Infectious Disease Center of Southwest Hospital, Third Military Medical University, Chongqing 400038, China. · Zhonghua Gan Zang Bing Za Zhi. · Pubmed #11242133 No free full text.

Abstract: OBJECTIVE: To explore the pathogenesis of hepatitis D virus by analyzing the clinic characteristics of 507 cases of hepatitis B (HB) with hepatitis D virus (HDV) infection. METHODS: The occurrence of different types of hepatitis, the prognosis, clinical features, major biochemistry results, and hepatitis virus marks were analyzed in 507 cases of HB with positive HDV and compared with 213 cases of HB with negative HDV. RESULTS: The incidence and the mortality of serious chronic hepatitis, severe hepatitis, and liver cirrhosis were all higher in the HB patients with positive HDV than negative one. The incidence of bleeding, ascites, hepat-coma complication, and the level of ALT were higher in HDV-positive patients than in HDV-negative patients (P<0.01 or P<0.05), and the changes of the major biochemistry results were more obvious than the same types of hepatitis B with negative HDV (P<0.01). The detection rate for HBeAg in serum of the patients positive for HDV was obviously lower than that of the patients negative for HDV(P<0.01). In patients with acute hepatitis, severe hepatitis, and liver cirrhosis, the expression of positive HDAg and negative HBeAG was obviously higher than that of positive HDAg and HBeAg (P<0.01 or P<0.05). CONCLUSIONS: After HDV infection, the incidences and poor prognosis of serious chronic hepatitis, severe hepatitis, and liver cirrhosis increase. HDV infection can inhibit the replication of HBV DNA or HBeAg expression. The effects of direct cytotoxicity of HDV on hepatocytes may play a major pathogenic role in acute hepatitis and in aggravating illness status to severe type.