No abstract

Despite recent advances in the chemotherapy of chronic hepatitis B (CHB), an effective viral suppression after cessation of therapy has not yet been achieved. To investigate whether hepatitis B virus (HBV)-specific T-cell responses are inducible and can contribute to the viral suppression after cessation of the therapy, we conducted a proof-of-concept study with a DNA vaccine comprising of most HBV genes plus genetically engineered interleukin-12 DNA (IL-12N222L) in 12 CHB carriers being treated with lamivudine (LAM). When the ex vivo and/or cultured IFN-g enzyme-linked immunospot (ELISPOT) assay was performed, the detectable HBV-specific IFN-g secreting T-cell responses were observed at the end of treatment and during a follow-up. These type 1T-cell responses, particularly CD4 + memory T-cell responses could be maintained for at least 40 weeks after the therapy and correlated with virological responses, but not with alanine aminotransferase elevation. Moreover, DNA vaccination under LAM treatment appeared to be well-tolerated and showed 50% of virological response rate in CHB carriers. Thus, a combination therapy of the DNA vaccine with chemotherapy may be one of new immunotherapeutic methods for the cure of CHB. Gene Therapy ( Patients with chronic HBV infection who showed remission also develop vigorous CTL and strong type 1T helper (Th1) immune responses that are comparable to those in patients who have a selflimited disease. 4 In contrast, the CTL and Th1 responses are undetectable or relatively weak in patients with chronic HBV infection. 3,5 Lamivudine (LAM) and adefovir dipivoxil as nucleoside analogues can suppress HBV replication effectively during treatment period, 6,7 but their use is limited by the high risk of viral relapse upon discontinuation even after long-term treatment.2 A restoration of HBV-specific CD4 + and CD8 + T-cell responses by LAM monotherapy was previously observed, but these T-cell responses were not only transient during treatment, but were also undetectable or very weak at the end of 1-year treatment. 8,9 It was recently reported that the inverse correlation between the number of antigen-specific interferon (IFN)-g producing CD4 + T cells and serum HBV DNA was observed during the treatment of LAM with recombinant interleukin-12 (IL-12) protein, but not detectable after the treatment. 10Therefore, further studies are needed to elucidate the relationship between T-cell responses and the suppression of viral relapse after stopping the therapy.DNA vaccine has the advantage of inducing both humoral and cellular immune responses, especially Th1 and CTL responses. HBV DNA vaccine was shown to induce strong T-cell responses, leading to the suppression of viral replication in HBV transgenic mice.11 In contrast, DNA immunization induced very weak T-cell

Background: Intradermal vaccination provides direct and potentially more efficient access to the immune system via specialised dendritic cells and draining lymphatic vessels. We investigated the immunogenicity and safety during 3 successive years of different dosages of a trivalent, inactivated, split-virion vaccine against seasonal influenza given intradermally using a microinjection system compared with an intramuscular control vaccine.

The pathogenesis of hepatitis C virus (HCV) infection is strongly influenced by the nature of the host's antiviral immunity. Counterintuitively, elevated serum concentrations of C-X-C chemokine 10 (CXCL10), a potent chemoattractant for antiviral T-cells and NK-cells, are associated with poor treatment outcomes in patients with chronic HCV. It has been reported that an N-terminal truncated form of CXCL10, generated by the protease dipeptidylpeptidase 4 (DPP4), can act as chemokine antagonist. We sought to investigate CXCL10 antagonism in the clinical outcome and evolution of acute HCV infection. We collected serial blood samples from 16 patients, at the clinical onset of acute HCV infection and at 12 standardized follow-up timepoints over the first year. Intact and truncated CXCL10 and DPP4 activity were quantified in all longitudinal samples. In addition, NK-cell frequency/phenotype, and HCV-specific T-cell responses were assessed. Subjects developing chronicity (n 5 11) had higher concentrations of CXCL10 (P < 0.001), which was predominantly in a truncated form (P 5 0.036) compared to patients who spontaneously resolved infection (n 5 5). Truncated CXCL10 correlated with HCV-RNA (r 5 0.40, P < 0.001) and DPP4 activity (r 5 0.53, P < 0.001). Subjects who resolved infection had a higher frequency of HCV-specific interferongamma (IFNc)-producing T-cells (P 5 0.017) and predominance of cytotoxic NK-cells (P 5 0.005) compared to patients who became chronic. Patients who became persistently infected had higher proportions of cytokine-producing NK-cells, which were correlated with concentrations of truncated CXCL10 (r 5 0.92, P < 0.001). Conclusion: This study provides the first evidence of chemokine antagonism during acute HCV infection. We suggest that the DPP4-CXCL10 axis inhibits antiviral innate and adaptive host immunity and favors establishment of viral persistence. (HEPATOLOGY 2014;60:487-496) A pproximately 3-4 million people are newly infected with hepatitis C virus (HCV) annually, of whom more than 80% will develop chronic infection.1 It is well established that the host immune response plays a key role in defining the clinical outcome of HCV infection. [2][3][4][5] However, the precise mechanisms responsible for the high rates of viral persistence are not fully understood. This paucity of knowledge stems from the shortage of appropriate in vivo / in vitro models and the difficulty of collecting samples during the acute phase, as these subjects are usually asymptomatic or symptomatic for a short period only.1 This has impeded temporal investigations analyzing the relationship between host immunity and the clinical course of HCV infection.C-X-C chemokine 10 (CXCL10; also known as interferon-gamma [IFNc]-inducible-protein-10 or

The importance of hepatitis B virus (HBV) genotypes for disease progression and response to interferon-alpha-based treatment is well established. While almost all patients in the Mediterranean area are infected with HBV genotype D, HBV genotype A is dominant in Northern Europe. However, the distribution of HBV genotypes is unknown for several Central and Eastern European countries. Data are described of 1313 HBsAg-positive patients recruited at 14 referral centers in eight countries. There were only very few cases of HBV genotype B, C, E, F, and H infection while HBV genotypes A and D were found in 42% and 48% of patients, respectively. Eight percent of patients had positive bands for more than one genotype using the hybridization assay. The frequency of genotype A was higher in Poland (77%) and the Czech Republic (67%) as compared to Hungary (47%), Lithuania (41%), Croatia (8%), and Germany (32%). In contrast, HBV genotype D was most frequent in Croatian, Romanian, and Russian patients with 80%, 67%, and 93% of cases, respectively. In conclusion, HBV genotype A versus D showed significantly different distribution patterns in Central and Eastern Europe which deserves consideration for national guidelines and treatment decisions.