Simulation and prediction of the adaptive immune response to influenza A virus infection.
The cellular immune response to primary influenza virus infection is complex, involving multiple cell types and anatomical compartments, and is difficult to measure directly. Here we develop a two-compartment model that quantifies the interplay between viral replication and adaptive immunity. The fidelity of the model is demonstrated by accurately confirming the role of CD4 help for antibody persistence and the consequences of immune depletion experiments. The model predicts that drugs to limit viral infection and/or production must be administered within 2 days of infection, with a benefit of combination therapy when administered early, and cytotoxic CD8 T cells in the lung are as effective for viral clearance as neutralizing antibodies when present at the time of challenge. The model can be used to investigate explicit biological scenarios and generate experimentally testable hypotheses. For example, when the adaptive response depends on cellular immune cell priming, regulation of antigen presentation has greater influence on the kinetics of viral clearance than the efficiency of virus neutralization or cellular cytotoxicity. These findings suggest that the modulation of antigen presentation or the number of lung resident cytotoxic cells and the combination drug intervention are strategies to combat highly virulent influenza viruses. We further compared alternative model structures, for example, B-cell activation directly by the virus versus that through professional antigen-presenting cells or dendritic cell licensing of CD8 T cells.
Lee
Ha Youn
HY
Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York 14642, USA.
Topham
David J
DJ
Park
Sung Yong
SY
Hollenbaugh
Joseph
J
Treanor
John
J
Mosmann
Tim R
TR
Jin
Xia
X
Ward
Brian M
BM
Miao
Hongyu
H
Holden-Wiltse
Jeanne
J
Perelson
Alan S
AS
Zand
Martin
M
Wu
Hulin
H
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D003198:Computer Simulation; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D007251:Influenza, Human / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008962:Models, Theoretical; D011237:Predictive Value of Tests
D000998:Antiviral Agents