title: The size of the viral inoculum contributes to the outcome of hepatitis B virus infection.
abstract: The impact of virus dose on the outcome of infection is poorly understood. In this study we show that, for hepatitis B virus (HBV), the size of the inoculum contributes to the kinetics of viral spread and immunological priming, which then determine the outcome of infection. Adult chimpanzees were infected with a serially diluted monoclonal HBV inoculum. Unexpectedly, despite vastly different viral kinetics, both high-dose inocula (10(10) genome equivalents [GE] per animal) and low-dose inocula (10 degrees GE per animal) primed the CD4 T-cell response after logarithmic spread was detectable, allowing infection of 100% of hepatocytes and requiring prolonged immunopathology before clearance occurred. In contrast, intermediate (10(7) and 10(4) GE) inocula primed the T-cell response before detectable logarithmic spread and were abruptly terminated with minimal immunopathology before 0.1% of hepatocytes were infected. Surprisingly, a dosage of 10(1) GE primed the T-cell response after all hepatocytes were infected and caused either prolonged or persistent infection with severe immunopathology. Finally, CD4 T-cell depletion before inoculation of a normally rapidly controlled inoculum precluded T-cell priming and caused persistent infection with minimal immunopathology. These results suggest that the relationship between the kinetics of viral spread and CD4 T-cell priming determines the outcome of HBV infection.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 920371, USA.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Asabe
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Wieland
authors.forename: Pratip K
authors.initials: PK
authors.lastname: Chattopadhyay
authors.forename: Mario
authors.initials: M
authors.lastname: Roederer
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Engle
authors.forename: Robert H
authors.initials: RH
authors.lastname: Purcell
authors.forename: Francis V
authors.initials: FV
authors.lastname: Chisari
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D004279:DNA, Viral / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D006509:Hepatitis B / Q000821:virology*; D006515:Hepatitis B virus / Q000378:metabolism* / Q000472:pathogenicity; D022781:Hepatocytes / Q000821:virology; D007371:Interferon-gamma / Q000378:metabolism; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000821:virology; D008099:Liver / Q000821:virology; D002679:Pan troglodytes
chemical_list: D004279:DNA, Viral; D007371:Interferon-gamma