Indeed, removal of circulating HBsAg by neutralizing anti-HBs mAb was reported to rescue the exhausted adaptive immune responses to hepatitis B vaccination, eventually leading to anti-HBs seroconversion in a murine model (43)

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Indeed, removal of circulating HBsAg by neutralizing anti-HBs mAb was reported to rescue the exhausted adaptive immune responses to hepatitis B vaccination, eventually leading to anti-HBs seroconversion in a murine model (43). HBV-vaccinated and subjects convalescent SRT1720 HCl from acute hepatitis B that show different properties and specificities. It is envisaged that such neutralizing mAb may be used as adjuvant treatment to reduce viral protein load, thus rescuing adaptive immunity in an effort to optimize the effect of antiviral drugs. Keywords: human monoclonal antibody, HBVhepatitis B virus, B cells, immune system, adaptive immunity Adaptive Immunity: The Main Player in HBV Control Hepatitis B virus (HBV) is responsible for acute and chronic hepatitis, potentially leading to cirrhosis and hepatocellular carcinoma [reviewed in (1)]. Hepatitis B can be effectively prevented by a prophylactic vaccine (2), whereas, antiviral drugs are virtually unable to eradicate the virus in chronically infected individuals despite efficient suppression of HBV DNA replication (3). Adaptive immunity plays a major role to provide long-term control of infection; however, the very low frequency of circulating HBV-specific T cells in chronic infection contributes to the inability to clear the virus (4). Indeed, HBV may settle for life in occult form in the nuclei of hepatocytes as minichromosome (covalently closed circular DNA, cccDNA), despite apparent recovery, potentially reactivating in case of immune suppression (5). The persistence of cccDNA in hepatocytes is the main hurdle to eradicate HBV infection. The problem is further compounded by the rapid decline of T-cell and B-cell responses as a result of exhaustion induced by Prox1 production of large amounts of excess HBV envelope proteins (6), largely resulting from integration of HBV DNA sequences into the host genome particularly in the HBeAg-negative chronic HBV infection [reviewed in (7)]. Of note, there is evidence that SRT1720 HCl increased levels of HBsAg may contribute the CD8+ T cell SRT1720 HCl dysfunction (8), and that HBsAg induces disruption of TLR9-mediated Interferon-alpha production by circulating plasmacytoid dendritic cells (9, 10). Moreover, HBV-specific T cells are mainly concentrated in the intrahepatic compartment together with a large number of HBV non-specific T cells (11), which may contribute to maintain liver inflammation via antigen-independent by-stander activation (12). Exhaustion caused by persistent exposure to high antigen concentrations provides the basis for T cell dysfunction, and results in up-regulation of programmed cell death protein 1 (PD-1) and other check-point molecules by HBV-specific CD8 T cells (13, 14). In line with this interpretation, the intensity of the T cell response appears inversely correlated with HBV DNA levels, with more intense HBV-specific responses detectable in patients with lower viral loads. B-cell responses also play a fundamental role in HBV infection. Antibodies specific for HBsAg are critical for the neutralization of free extracellular HBV, thus preventing viral entry into susceptible hepatocytes (15). However, antibodies are unable to eradicate intracellular virus, a task fulfilled by MHC class I-restricted virus-specific CD8+ T cells by lytic and non-lytic mechanisms (16). Anti-HBs antibodies are also produced during the chronic phase of the infection in minimal amount, most likely complexed by the large amount of the HBV envelope proteins present in the serum. Antibodies SRT1720 HCl to the viral nucleoprotein, anti-HBc and anti-HBe, instead persist during chronic infection and detection of anti-HBe is linked to the emergence of the e-minus variant. The finding of undetectable HBV DNA by standard assays and anti-HBc in the absence of HBsAg SRT1720 HCl is taken as surrogate evidence of occult HBV infection (17). Current evidence supports the view that a coordinated activation of both T and B cells is critical for eradication of infection. Of note, CD4+ T cells control CD8+ T cell activity and antibody production (18), and the inability of the infected host to mount robust virus-specific antibody responses correlates with a premature loss of CD4+ T cell responsiveness during the establishment of viral persistence in a chimpanzee model of HBV infection (19, 20). Interestingly, sera containing high-titer anti-HBs antibodies provide protection upon exposure to HBV (21), the eradication of which is closely related to the development of neutralizing anti-HBs antibodies. The.