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本帖最后由 StephenW 于 2012-3-7 11:30 编辑
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Novel Mechanism of Antibodies to Hepatitis B Virus in Blocking Viral Particle Release from Cells
Avidan U. Neumann,1 Sandra Phillips,2 Idit Levine,1 Samreen Ijaz,3 Harel Dahari,1,4 Rachel Eren,5 Shlomo Dagan,5 and Nikolai V. Naoumov2
1Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
2Institute of Hepatology, University College London, United Kingdom
3Hepatitis Laboratory, Health Protection Agency, Colindale, United Kingdom
4Department of Medicine, Section of Hepatology, University of Illinois at Chicago, Chicago, IL USA
5XTL Biopharmaceuticals Ltd., Kiryat Weizmann Science Park, Rehovot, Israel
Corresponding Author: Nikolai V. Naoumov, MD; Immunology and Infectious Diseases, Novartis Pharma AG, Basel 4002, Switzerland, Tel: +41-7959 29281;
Email: [email protected]
Rachel Eren is currently at Andromeda Biotech Ltd, Yavne 81227, Israel, [email protected]. Shlomo Dagan is currently at Andromeda Biotech Ltd, Yavne 81227, Israel, [email protected]. Nikolai V. Naoumov is currently affiliated with Novartis Pharma, Basel, Switzerland, [email protected]
 The publisher's final edited version of this article is available at Hepatology
Abstract
Antibodies are thought to exert antiviral activities by blocking viral entry into cells and/or accelerating viral clearance from circulation. In particular, antibodies to hepatitis B virus (HBV) surface antigen (HBsAg) confer protection, by binding circulating virus. Here, we used mathematical modeling to gain information about viral dynamics during and after a single or multiple infusions of a combination of two human monoclonal anti-HBs (HepeX-B™) in patients with chronic hepatitis B. The antibody HBV-17 recognizes a conformational epitope, while antibody HBV-19 recognizes a linear epitope on the HBV surface antigen. The kinetic profiles of the decline of serum HBV DNA and HBsAg revealed partial blocking of virion release from infected cells as a new antiviral mechanism, in addition to acceleration of HBV clearance from the circulation. We then replicated this approach in vitro, using cells secreting HBsAg, and compared the prediction of the mathematical modeling obtained from the in vivo kinetics. In-vitro, HepeX-B™ treatment of HBsAg-producing cells showed cellular uptake of antibodies resulting in intracellular accumulation of viral particles. Blocking HBsAg secretion continued also after HepeX-B™ was removed from the cell culture supernatants.
Conclusion
These results identify a novel antiviral mechanism of antibodies to HBsAg involving prolonged blocking of the hepatitis B virus and HBsAg subviral particles release from infected cells. This may have implications in designing new therapies for patients with chronic HBV infection and may also be relevant in other viral infections.
Keywords: Hepatitis B virus, anti-HBs, antiviral antibodies, viral kinetics, immunotherapy
Viruses elicit a range of antiviral antibodies, but only some of these have direct antiviral activity and are referred as neutralizing antibodies, as they render virions non-infectious by blocking viral entry into cells (1). Such antibodies bind to epitopes that interfere with the interaction of the viral surface protein and its receptor by steric hindrance (2), by targeting directly the receptor-binding site on virus (3), or by inducing conformational changes that abrogate the functionality of the viral surface protein (4). In addition, the antiviral activities of antibodies against virus particles in the circulation can include clearance via Fc-mediated effector systems, such as complement-dependent virolysis or phagocytosis (5).
In hepatitis B virus (HBV) infection, antibodies directed to a conserved region, a-determinant, of the HBV surface antigen (HBsAg), are known to confer protection by high-affinity binding of HBsAg, the main component of the virus envelope, as well as the 22-nm subviral particles (6). The efficacy of antibodies to HBsAg (anti-HBs) in preventing HBV infection has been established both when given as passive immunoprophylaxis – for example, to prevent mother-to-child HBV transmission or to prevent HBV reinfection of the liver graft following liver transplantation (7), as well as by the success of universal active immunization using recombinant HBsAg, resulting in high anti-HBs titres (8). The mechanisms of anti-HBs protection are not understood, although the common belief is that these are based on binding HBV particles in circulation, thus preventing the infection of liver cells. According to this paradigm, cells that have already been infected will not be affected by anti-HBs. Importantly, the protection achieved by anti-HBs, at least in the liver transplant setting, is not sterile as HBV DNA is detectable in the new liver even in cases with effective prophylaxis (9).
Recently, in vitro experiments have shown that HBs-specific IgG is internalized into hepatocyte-derived cell lines and inhibits the secretion of HBsAg and virions from these cells (10). The HBsAg and anti-HBs were co-localized within the cells, and the specificity of intracellular HBsAg-anti-HBs interaction was further demonstrated by abrogating the anti-HBs inhibitory effect in cell transfected with HBV genomes expressing antibody-escape mutant HBsAg (10). To investigate further the phenomenon of intracellular blocking of HBV release by antibodies and its potential for therapeutic application, we analyzed both in vivo and in vitro the effect of two human monoclonal antibodies to HBsAg - HBV-Ab17 and HBV-Ab19, that have been shown to have high neutralizing activity against HBV (11, 12). We used mathematical modeling of serum HBV DNA and HBsAg levels to gain information about viral dynamics during a single or multiple infusions of a combination of the two monoclonal anti-HBs (HepeX-B™) in patients with chronic hepatitis B. We then replicated this approach in vitro, using cells secreting HBsAg, and compared the prediction of the mathematical modeling obtained from the in vivo kinetics.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086357/
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发表于 2012-3-7 11:24
