Effect of 48-week pegylated interferon α-2a or nucleos(t)ide analogue therapy on renal function in Chinese patients with chronic hepatitis B.

BACKGROUND: Controversy remains as to whether antiviral agents contribute to renal dysfunction in patients with chronic hepatitis B virus (HBV) infection. Thus, the aim of study was to analyze the changes in renal function of chronic hepatitis B (CHB) patients in response to anti-HBV therapy and the association with treatments. METHOD: We performed a retrospective observational cohort study to investigate factors associated with renal function in 249 Chinese CHB patients who were treated with pegylated interferon α-2a (PEG-IFN-α-2a) or nucleos(t)ide analogues for 48 weeks. Changes of estimated glomerular filtration rate (eGFR), which was computed with both the Chronic Kidney Disease Epidemiology Collaboration and the Modification of Diet in Renal Disease formulas, were tested by repeated measures One-way analysis of variance within groups. A linear mixed effects model for repeated measures was also used to evaluate the association between baseline information and eGFR changes over time in all enrolled patients. The model considered the baseline age, sex, HBV DNA, aminotransferase, blood urea nitrogen, treatment group, time, and group-by-time interaction as fixed effects and incorporated random effects for individual subjects. RESULTS: The eGFR increased in patients given PEG-IFN-α-2a, decreased in patients given adefovir, but remained stable in patients given entecavir. Age and blood urea nitrogen were significant negative predictive factors for eGFR changes. CONCLUSION: In real-life study, PEG-IFN-α-2a therapy in CHB patients increased eGFR, thus may associate with renoprotective effects when compared with adefovir or entecavir therapies.

A proinflammatory role for interleukin-22 in the immune response to hepatitis B virus.

BACKGROUND & AIMS: T-helper (Th)17 cells that secrete interleukin (IL)-22 have immunomodulatory and protective properties in the liver and other tissues. IL-22 induces expression of proinflammatory genes but is also mitogenic and antiapoptotic in hepatocytes. Therefore, it could have multiple functions in the immune response to hepatitis B virus (HBV). METHODS: We examined the role of IL-22 in regulating liver inflammation in HBV transgenic mice and measured levels of IL-22 in HBV-infected patients. RESULTS: In HBV transgenic mice, injection of a single dose of IL-22 increased hepatic expression of proinflammatory genes but did not directly inhibit virus replication. When splenocytes from HBV-immunized mice were transferred into HBV transgenic mice, the severity of the subsequent liver damage was ameliorated by neutralization of IL-22. In this model, IL-22 depletion did not affect interferon gamma-mediated noncytopathic inhibition of virus replication initiated by HBV-specific cytotoxic T cells, but it significantly inhibited recruitment of antigen-nonspecific inflammatory cells into the liver. In patients with acute HBV infections, the percentage of Th17 cells in peripheral blood and concentration of IL-22 in serum were significantly increased. CONCLUSIONS: IL-22 appears to be an important mediator of the inflammatory response following recognition of HBV by T cells in the liver. These findings might be relevant to the development of cytokine-based therapies for patients with HBV infection.

Dysregulation of the ß3 integrin-VEGFR2 complex in Hantaan virus-directed hyperpermeability upon treatment with VEGF.

Hantaviruses infect human endothelial cells (ECs) and are known to cause vascular-permeability-based diseases, including hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). The αvß3 integrins, which are highly expressed on the surface of ECs, serve as hantavirus receptors. Specifically, the ß3 integrin and vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) form a functional complex and interact with each other. Signaling through this complex causes cytoskeletal reorganization, which is one of the most important mechanisms underlying hyperpermeability. In this study, we show that VEGF dramatically enhances Hantaan virus (HTNV)-directed permeability and increases the reorganization of the cytoskeleton and the disruption of junctional organizations in an EC monolayer at 3 days postinfection. HTNV infection reduced the effect of VEGF on adhesion, migration, and the upregulation of ß3 expression, but the infection alone upregulated the expression of ß3 and VEGFR2. These results indicate that in addition to its role in blocking ß3 integrin activation as reported previously, HTNV blocks the function of the complex of VEGFR2 and ß3 integrin, and the dysfunction of the complex may contribute to cytoskeletal reorganization in an HTNV-directed hyperpermeability response to VEGF.

A human immunodeficiency virus-seronegative acquired immunodeficiency syndrome patient with opportunistic infections: A case report.

BACKGROUND: In rare cases, people living with chronic human immunodeficiency virus (HIV) infection do not develop antibodies despite demonstrable infection. Delayed or missed diagnosis of HIV infection leads to a lack of timely therapy, resulting in rapid disease progression with opportunistic infections or malignancies. CASE REPORT: A 44-year-old Chinese man presented with sore throat, oral leukoplakia, fever, dyspnoea and diffuse ground glass-like lesions in both lungs. Serum cytomegalovirus DNA was detectable, and CD4+ T-cell count was low. The patient was suspected of being a person living with HIV despite of the repeatedly negative HIV antibody tests using enzyme-linked immunsorbent assay and Western blot. Subsequently, high-plasma HIV RNA viral load was found on two repeated tests, while HIV DNA was also positive. Thus, the patient was confirmed as presenting with HIV-seronegative acquired immunodeficiency syndrome (AIDS). The symptoms improved in response to effective anti-fungal and anti-retroviral therapy after diagnosis. CONCLUSION: This is the third reported case of an HIV-seronegative AIDS patient in China, which are also rarely reported globally. HIV nucleic acid testing is important to screen out HIV infection, especially in those who present with severe immunodeficiency but remain HIV serogenative.

Therapeutic effect of RANTES-KDEL on inhibition of HIV-1 in CD34(+) human hematopoietic stem cells (hHSC).

Cell surface receptors, such as the CCR5 chemokine receptors, represent key determinants of the human immunodeficiency virus type 1 (HIV-1) entry into target cells. The CC-chemokine, RANTES (regulated upon activation, normal T-cell expressed and secreted), a ligand for CCR5, have been targeted to the lumen of endocytoplasmic reticulum (ER) using a KDEL (ER-retention signal) fusion termed RANTES-KDEL and this construct was found to prevent effectively transport of newly synthesized CCR5 to the cell surface. Lentiviral vectors have emerged as potent and versatile tools of gene transfer for basic and applied research are able to transduce nondividing cells and maintain sustained long-term expression of transgenes. For this reason, an HIV-based lentiviral vector expressing RANTES-KDEL, pLenti6/V5-R-K, was constructed and then cotransfected with the ViraPower Packaging Mix (pLP1, pLP2, and pLP/VSVG) into 293FT cells to produce a replication-incompetent lentivirus stock. The lentiviral stock was titrated using HeLa cells, and the expression of the gene of interest, RANTES, was detected by indirect immunofluorescence. Based on the above results, the lentiviral stock was transduced into CD34(+) human hematopoietic stem cells (hHSC) separated magnetically from the cord blood (the purity was 96.8% evaluated by flow cytometry). Finally, the levels of p24 in the cultures of pLenti6/V5-R-K-transduced CD34(+) hHSC were detected after infection by HIV-1 DP1 (a R5-tropic HIV-1 strain, which was isolated by the Centers for Disease Control and Prevention of China in Henan province in 2000 from a Chinese man who had asymptomatic HIV-1 infection with a history of blood transfusions). It was shown that pLenti6/V5-R-K transduction inhibited expression of the DP1 p24 antigen by 51%, 58% and 60% on the 4th, 7th and 10th day respectively (P<0.05).

The short hairpin RNA driven by polymerase II suppresses both wild-type and lamivudine-resistant hepatitis B virus strains.

BACKGROUND: Chronic infection with hepatitis B virus (HBV) is widespread because of the limited availability of therapeutic treatments. Although previous reports have suggested that RNA interference has promise as a treatment for HBV infection, further studies of long-term and off-target drug effects on HBV, especially on drug-resistant strains of HBV, are needed. Therefore, seven vectors that express short hairpin RNAs (shRNAs), driven by the polymerase II promoter, pSilencer4.1/HBV, were constructed to target open reading frames (ORFs) of the HBV C and S genes from wild-type and drug-resistant strains. Treatment efficiency was also assessed. METHODS: The pSilencer4.1/HBV vectors were investigated in HepG2.2.15 cells and transgenic mice that consistently produce wild-type HBV. Additionally, vectors that produce a lamivudine-resistant strain of HBV were developed and cotransfected, along with pSilencer/HBV, into both HepG2 cells and mice. The effects of polymerase-II-driven pSilencer4.1/HBV were compared with those of polymerase-III-driven pSilencer3.1/HBV at both the gene and protein level. RESULTS: pSilencer4.1/HBV inhibited the expression of viral protein, DNA and HBV subtype ayw mRNA in both HepG2.2.15 cells and transgenic mice. Toxicity, as well as off-target effects, did not occur after a short- to medium-term examination. Moreover, an HBV strain resistant to lamivudine, subtype adr, was suppressed by shRNA in both HepG2 cells and mice. In contrast to polymerase III, vectors that used polymerase II could drive efficient silencing without off-target effects. CONCLUSIONS: Silencing by shRNA dramatically inhibited HBV expression and replication regardless of strain type. ShRNA could therefore be a promising treatment for HBV infection.

Modulation of Tim-3 Expression by Antigen-Dependent and -Independent Factors on T Cells from Patients with Chronic Hepatitis B Virus Infection.

T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) was up-regulated on viral specific T cells and contributed to T cells exhaustion during chronic hepatitis B virus (HBV) infection. However, modulation of Tim-3 expression was still not fully elucidated. To evaluate the potential viral and inflammatory factors involved in the inductor of Tim-3 expression on T cells, 76 patients with chronic HBV infection (including 40 chronic hepatitis B [CHB] and 36 asymptomatic HBV carriers [AsC]) and 40 of normal controls (NCs) were enrolled in this study. Tim-3 expressions on CD4+ and CD8+ T cells were assessed in response to HBV-encoding antigens, HBV peptide pools, and common γ-chain (γc) cytokines stimulation by flow cytometry. HBV peptides and anti-CD3/CD28 directly induced Tim-3 expression on T cells. γc cytokines also drive Tim-3 up-regulations on both CD4+ and CD8+ T cells in patients with chronic HBV infection. However, γc cytokines did not enhance the Tim-3 inductions by either anti-CD3/CD28 or HBV peptides stimulation. Furthermore, γc cytokines-mediated Tim-3 induction could not be abrogated by γc cytokine receptor-neutralizing antibodies. The current results suggested that elevation of Tim-3 expression on T cells could be regulated by both antigen-dependent and -independent manner in patients with chronic HBV infection. The role of γc cytokines in modulation of inhibitory pathway might be evaluated as immunotherapies in humans.

Notch Signaling Contributes to Liver Inflammation by Regulation of Interleukin-22-Producing Cells in Hepatitis B Virus Infection.

The mechanism of hepatitis B virus (HBV) induced liver inflammation is not fully elucidated. Notch signaling augmented interleukin (IL)-22 secretion in CD4+ T cells, and Notch-IL-22 axis fine-tuned inflammatory response. We previously demonstrated a proinflammatory role of IL-22 in HBV infection. Thus, in this study, we analyzed the role of Notch in development of IL-22-producing cells in HBV infection by inhibition of Notch signaling using γ-secretase inhibitor DAPT in both hydrodynamic induced HBV-infected mouse model and in peripheral blood cells isolated from patients with HBV infection. mRNA expressions of Notch1 and Notch2 were significantly increased in livers and CD4+ T cells upon HBV infection. Inhibition of Notch signaling in vivo leaded to the reduction in NKp46+ innate lymphoid cells 22 (ILC22) and lymphoid tissue inducer 4 (LTi4) cells in the liver. This process was accompanied by downregulating the expressions of IL-22 and related proinflammatory cytokines and chemokines in the liver, as well as blocking the recruitment of antigen-non-specific inflammatory cells into the liver and subsequent liver injury, but did not affect HBV antigens production and IL-22 secretion in the serum. Furthermore, IL-22 production in HBV non-specific cultured CD4+ T cells, but not HBV-specific CD4+ T cells, was reduced in response to in vitro inhibition of Notch signaling. In conclusion, Notch siganling appears to be an important mediator of the liver inflammation by modulating hepatic ILC22. The potential proinflammatory effect of Notch-mediated ILC22 may be significant for the development of new therapeutic approaches for treatment of hepatitis B.

Toll-like receptor 2 promotes T helper 17 cells response in hepatitis B virus infection.

PURPOSE: Innate and adaptive immune responses play vital roles in initiating and maintaining the immunological homeostasis in both physiological and pathological processes. However, the expression and function of the important cells and molecules as well as their interaction in hepatitis B virus (HBV) infection has not been well elucidated. The aim of the current study was to determine the pattern of Toll-like receptor 2 (TLR2) in T cells in HBV infection and the function of TLR2 in regulation of T helper 17 (Th17) cells response. METHODS: Thirty-four patients with HBV infection (ten acute and twenty-four chronic) were enrolled. HBV-specific and -nonspecific Th17 cells and TLR2 expression in T cells were analyzed by flow cytometry. The function of TLR2 agonist for induction of IL-17 production was also determined. RESULTS: HBV-specific and -nonspecific IL-17 secretion in CD4(+) (Th17 cells) and CD8(+) T cells was significantly elevated in chronic HBV infection. Viral-specific TLR2 expression in CD4(+), CD8(+), and Th17 cells was also remarkably increased in patients with chronic hepatitis B. Moreover, TLR2 agonist Pam3Csk4 directly activated Th17 cells response without antigen stimulation in HBV infection. CONCLUSION: TLR2, which traditionally associated with innate immunity, might also promote Th17 cells response in HBV infection. The function of TLRs in regulation of adaptive immune response in HBV infection, which might play an important role in persistent HBV infection.

Hepatic stem cells: existence and origin.

Stem cells are not only units of biological organization, responsible for the development and the regeneration of tissue and organ systems, but also are units in evolution by natural selection. It is accepted that there is stem cell potential in the liver. Like most organs in a healthy adult, the liver maintains a perfect balance between cell gain and loss. It has three levels of cells that can respond to loss of hepatocytes: (1) Mature hepatocytes, which proliferate after normal liver tissue renewal, less severe liver damage, etc; they are numerous, unipotent, "committed" and respond rapidly to liver injury. (2) Oval cells, which are activated to proliferate when the liver damage is extensive and chronic, or if proliferation of hepatocytes is inhibited; they lie within or immediately adjacent to the canal of Hering (CoH); they are less numerous, bipotent and respond by longer, but still limited proliferation. (3) Exogenous liver stem cells, which may derive from circulating hematopoietic stem cells (HSCs) or bone marrow stem cells; they respond to allyl alcohol injury or hepatocarcinogenesis; they are multipotent, rare, but have a very long proliferation potential. They make a more significant contribution to regeneration, and even completely restore normal function in a murine model of hereditary tyrosinaemia. How these three stem cell populations integrate to achieve a homeostatic balance remains enigmatic. This review focuses on the location, activation, markers of the three candidates of liver stem cell, and the most importantly, therapeutic potential of hepatic stem cells.

Successful rescuing a pregnant woman with severe hepatitis E infection and postpartum massive hemorrhage.

AIM: To sum up the experience of the successful therapy for the severe hepatitis of pregnant woman with postpartum massive hemorrhage. METHODS: The advanced therapeutic methods including the bilateral uterine artery embolism, hemodialysis and artificial liver support therapy were performed with comprehensive medical treatments and the course of the successful rescuing the patient was analyzed. RESULTS: Through the hospitalization of about two mouths the patient and her neonatus had gotten the best of care in our department and pediatric department separately. Both of them were discharged in good condition. CONCLUSION: The key points for a successful therapy of the pregnant woman with severe hepatitis are termination of the pregnancy and the control of their various complications. It was suggested that the proper combination of these measures of modern therapy would race against time for renewing of hepatic and renal functions.

[The relationship between cellular infection by Hantaan virus and expression of beta3 integrin].

OBJECTIVE: To investigate the relationship between cellular entry of Hantaan virus (HTNV) and expression of beta3 integrin in beta3-integrin-deficient and HTNV-insusceptible China hamster ovary (CHO) cells. METHODS: Eukaryotic expression vector encoding human integrin beta3 and eukaryotic expression vector harboring human integrin alphav or alphaIIb subunit cDNA were transfected into HTNV non-permissive CHO cells individually or collectively. Screening for stable transfectant clones was performed using G418 selective (culture medium. The exogenous gene expression was analyzed qualitatively and quantitatively by immunofluorescence assay (IFA) and flow cytometry (FCM). Various modified CHO cells and untransfected CHO cells were infected using HTNV A9. At various time points after infection, HTNV antigens in infected cells were detected qualitatively and quantitatively by IFA, FCM. RESULTS: Highly-effective surface expression of beta3 integrin was measured in CHO/alphavbeta3 and CHO/alphaIIbbeta3, while weaker surface expression was detected in CHO/beta3 (P < 0.05). Expression of alphav or alphaIIb integrin in the individually transfected group was significantly lower than in the cotransfected group (P < 0.01) and the sites of localization changed. In contrast, effective surface expression was not seen when pcDNA3 was transfected alone. The infection rate of CHO/alphavbeta3 (60.1%) and CHO/alphaIIbbeta3 (55. 9%) cells were significantly higher than that of CHO/beta3 (38.7%) cells, while the infection rate of CHO/beta3 was significantly higher than that of CHO/alphav, CHO/pcDNA3 and CHO cells respectively. There was a close relationship between the positive percentage of HTNV A9-infected cells and expression of beta3 integrin. CONCLUSION: These results indicated that cellular entry of HTNV was related to the expression of beta3 integrin.

A fusion DNA vaccine encoding middle version of HBV envelope protein fused to interleukin-21 did not enhance HBV-specific immune response in mice.

DNA vaccination can generate both humoral and cellular immunity, resulting in potential prophylactic and therapeutic vaccines in variety of conditions, including hepatitis B virus (HBV) infection. Fusion of cytokine gene is one of the ways to increase the immunogenicity of DNA vaccine. Interleukin (IL)-21 has been demonstrated to play an immunomodulatory role in HBV infection. Thus, we aimed to investigate the ability of IL-21 in the regulation of middle version of HBV envelop protein (MS) DNA vaccine. Fusion plasmid encoding IL-21 linked with MS was constructed. Normal and HBV transgenic mice were immunized by plasmid. pcDNA-IL-21/S2S induced a comparable level of anti-HBs antibody and HBsAg-specific CD8+ T-cell response with pcDNA-S2S. Furthermore, the level of circulating HBsAg was decreased by induction of anti-HBs antibody and HBsAg-specific CD8+ T-cell response to both pcDNA-IL-21/S2S and pcDNA-S2S vaccination in HBV transgenic mice. Thus, immunization with DNA vaccine encoding HBV MS protein induced both T- and B-cell response by targeting the specific antigen. Furthermore, it was also revealed that MS DNA vaccination could break immune tolerance in HBV transgenic mice. But IL-21 did not strengthen immune response induced by HBV DNA immunization. Our study suggested that MS-expressing plasmid may be useful for both preventive and therapeutic methods in HBV infection. However, IL-21 does not improve the immunogenicity and efficacy of MS DNA vaccination, and thus may not be used as a therapeutic marker for chronic hepatitis B.

Expression profiles of circulating cytokines, chemokines and immune cells in patients with hepatitis B virus infection.

BACKGROUND: Immune cells and molecules play a vital role in initiating, maintaining, regulating immunological homeostasis and inflammation in many pathological and physiological processes; however, the changes on expressions and functions of these cells and molecules in hepatitis B virus (HBV) infection have not been elucidated well. OBJECTIVES: The current study aimed to determine the expression pattern of different cytokines, chemokines, immune cells in HBV infection and their association with disease progression. PATIENTS AND METHODS: Sixty-nine patients with chronic HBV infection were enrolled. Five immune cell subsets and 46 cytokines and chemokines were analyzed by flow cytometry and Luminex 200. RESULTS: In comparison to healthy individuals and asymptomatic HBV carriers, expression of CXCL9, CXCL10, CXCL11, and IL-10 were elevated in patients with chronic active HBV and had positive correlation with ALT levels. In contrast, G-CSF, MCP-3, and IFN-γ levels were significantly decreased in patients with chronic active HBV infection in contrast to carriers and healthy individuals; however, these down regulations did not show any correlation with either virological findings or liver inflammation. Although the proportion of CD4(+) CD25 (high) regulatory T cells (Tregs) was higher in patients with HBV infection than in healthy controls, no correlations were found between Tregs and other cytokines or chemokines. CONCLUSIONS: CXCR3-associated chemokines might contribute to liver inflammation in chronic hepatitis B, while MCP-3 and G-CSF were inhibited by HBV infection. Host immune response was suppressed as manifested by an increase in CD4(+) CD25(high) Tregs and IL-10 as well as a decrease in IFN-γ. Exploiting the expression pattern of cytokine and chemokine may help to develop a better understanding of chronic HBV infection pathogenesis.

Telbivudine plus adefovir therapy for chronic hepatitis B patients with virological breakthrough or genotypic resistance to telbivudine.

BACKGROUND/AIM: There is very limited experience in the management of telbivudine (LdT)-associated virological breakthrough (VBT) and resistance in the treatment of chronic hepatitis B (CHB) patients, and the guideline recommendations are primitively based on the general principles of rescue therapy to nucleos(t)ide analog resistance. The aim of this study is to determine the effect of the addition of adefovir (ADV) in hepatitis B e antigen (HBeAg)-positive CHB patients with VBT or resistance to LdT. METHODS: Thirty-seven CHB patients with confirmed VBT and 31 patients with genotypic resistance to LdT were enrolled and thereafter treated with a combination of LdT and ADV for 12 months. RESULTS: Combination therapy was safe and the majority of patients tolerated the therapy. LdT+ADV led to rapid decreases in viral loads, and viral replications were persistently suppressed, with 2.17 (VBT) and 2.31 (resistance) log(10) copies/ml reductions 12 months after rescue therapy, respectively. The rates corresponding to virological and biochemical responses were similar between the two groups at the end of observations (70.3 vs. 74.2% for virological response, P=0.720; 64.0 vs. 65.5% for biochemical response, P=0.907). The cumulative rates of serological responses were higher in patients with VBT than in those with resistance (35.1 vs. 9.67% for HBeAg loss, P=0.014; 10.8 vs. 3.23% for HBeAg/anti-HBe seroconversion, P=0.233). CONCLUSION: LdT and ADV combination therapy led to significant decreases in serum hepatitis B virus DNA levels and normalization of alanine aminotransferase levels in patients with VBT or genotypic resistance to LdT. This rescue strategy was also associated with a higher rate of HBeAg serological outcomes in patients with confirmed LdT-related VBT.

[Immune response to HBsAg can not be enhanced with B7-H1 protein vaccine].

AIM: To observe the immunization effect to HBsAg by B7-H1 protein vaccine in transgenic mice, and to explore new methods for the treatment of chronic hepatitis B. METHODS: After the joint immunization in HBV transgenic mice with different doses of hepatitis B virus (HBV) vaccine and B7-H1 protein, the anti-B7-H1 antibody titors, Th1 type of cytokines (IFN-γ and IL-2) from the spleen cells of mice, the number of the T cells secreting IFN-γ and the number of the mice lymphocyte proliferation were measrued by ELISA, ELISPOT and MTT technique respectively, to compare the immune effect of different immune methods and regimen. RESULTS: The immune plans were completed successfully. The anti-B7-H1 antibody was detected in the fifth week after immunization with B7-H1 vaccine, at the same time no obvious difference of antibodies titors between groups were found. IL-2 and the number of T cells secreting IFN-γ were significantly reduced(P<0.05)in joint immunization group with B7-H1 protein and HBsAg, but no difference in other immune tests, such as IFN-γ, lymphocyte proliferation. CONCLUSION: A lower doses of HBsAg can cause the secretion of Th1 type of cytokines and lymphocyte proliferation. B7-H1 protein vaccines have a better immunogetic effect for HBV transgenic mice, but can notupregulate the immune response to HBsAg.

[The induced IL-21 levels in CD4(+) T cells of peripheral blood from the different clinical types of patients infected with hepatitis B virus].

AIM: To investigate the levels of interleukin (IL)-21 in CD4(+);T cells of peripheral blood from the different types of patients infected with hepatitis B virus (HBV) and elucidate its role in the hepatitis B pathogenesis. METHODS: Peripheral blood mononuclear cells (PBMCs) from the patients infected with HBV and healthy individuals were stimulated with or without PMA coupled with ionomycin. The levels of IL-21 in CD4(+) T cells and Th17 cells were analyzed by flow cytometry. RESULTS: PMA and ionomycin induced the expression of IL-21, and IL-21 was mainly produced by CD4(+); T cells, but IL-17A(+) IL-21(+) CD4(+) T cells were not detected. The frequencies of IL-21(+) CD4(+) T cells in the patients of acute hepatitis B and chronic asymptomatic HBV carriers were higher than in healthy controls and severe chronic hepatitis B patients; there were no remarkable differences in the proportion of Th17 cells among the different groups of patients. Furthermore, the proportion of IL-21(+) CD4(+) T cells correlated with Th17 cells in all groups except for the acute hepatitis B patients. CONCLUSION: IL-21 levels, which correlated with Th17 cells, were different in CD4(+);T cells from the different types of patients infected with hepatitis B virus (HBV). The results showed that IL-21 may play a role in the hepatitis B pathogenesis.