The Size of the Viral Inoculum Contributes to the Outcome of Hepatitis B Virus Infection

被引:250
作者
Asabe, Shinichi [1 ]
Wieland, Stefan F. [1 ]
Chattopadhyay, Pratip K. [2 ]
Roederer, Mario [2 ]
Engle, Ronald E. [3 ]
Purcell, Robert H. [3 ]
Chisari, Francis V. [1 ]
机构
[1] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA
[2] NIAID, Immuno Technol Sect, Immunol Lab, Vaccine Res Ctr,NIH, Bethesda, MD 20892 USA
[3] NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA
基金
美国国家卫生研究院;
关键词
CD8(+) T-CELLS; LYMPHOCYTE RESPONSIVENESS; CD8-T-CELL MEMORY; RNA REPLICATION; PD-1; EXPRESSION; CD4-T-CELL HELP; HBV INFECTION; EXHAUSTION; TOLERANCE; IMMUNITY;
D O I
10.1128/JVI.00867-09
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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(0) 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.
引用
收藏
页码:9652 / 9662
页数:11
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