Novel mechanism of antibodies to hepatitis B virus in blocking viral particle release from cells.
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 single or multiple infusions of a combination of two human monoclonal anti-HBs (HepeX-B) antibodies in patients with chronic hepatitis B. The antibody HBV-17 recognizes a conformational epitope, whereas antibody HBV-19 recognizes a linear epitope on the HBsAg. 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 of HBsAg secretion also continued after HepeX-B was removed from the cell culture supernatants.


CONCLUSIONS
These results identify a novel antiviral mechanism of antibodies to HBsAg (anti-HBs) involving prolonged blocking of the HBV 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.
Neumann
Avidan U
AU
Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
Phillips
Sandra
S
Levine
Idit
I
Ijaz
Samreen
S
Dahari
Harel
H
Eren
Rachel
R
Dagan
Shlomo
S
Naoumov
Nikolai V
NV
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004279:DNA, Viral / Q000097:blood; D000939:Epitopes / Q000276:immunology; D006514:Hepatitis B Surface Antigens / Q000097:blood / Q000276:immunology*; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology / Q000821:virology; D006801:Humans; D008962:Models, Theoretical; D014771:Virion / Q000187:drug effects*
D000911:Antibodies, Monoclonal; D004279:DNA, Viral; D000939:Epitopes; D006514:Hepatitis B Surface Antigens; C470329:monoclonal antibody XTL001