Mathematical modeling of primary hepatitis C infection: noncytolytic clearance and early blockage of virion production.
OBJECTIVE
Although hepatitis C virus kinetics and immune determinants during primary infection have been described, the virus-host interplay is not fully understood. We used mathematical modeling to elucidate and quantify virus-host dynamics.


METHODS
Ten chimpanzees were infected intrahepatically with H77-RNA (n = 3) or intravenously with infected serum. Blood samples were taken 1-3 times per week for 6 months. A new model was fitted to the observed HCV RNA and alanine aminotransferase (ALT) kinetics.


RESULTS
After infection, viral levels increased in a biphasic manner with a transient decline in between. This can be explained by a partial block (mean, 91%) of virion production, possibly due to an endogenous type I interferon response. After reaching maximum levels, a long viral plateau (mean, 6.1 log cp/mL) can be explained by blind homeostasis and lack of susceptible cells. Modest elevations in ALT levels (21-93 IU/L) were concurrently observed, indicating a shorter half-life of infected versus noninfected hepatocytes (mean ratio, 2.6). Following the ALT flare, viral titers rapidly declined to a lower (mean, 4.5 log cp/mL; n = 6) or undetectable level (n = 4). This decline is compatible with increased cell death (mean minimal estimate half-life, 28.7 days) and noncytolytic clearance (mean maximal estimate half-life, 24.1 days) of infected cells.


CONCLUSIONS
Our results quantify virus-host dynamics during primary HCV infection and suggest that endogenous type I interferon slows virus production in the early acute phase. Partial or effective virus control correlates with the half-life of infected cells regulated by both cytolytic and noncytolytic mechanisms.
Dahari
Harel
H
Faculty of Life Science, Bar-Ilan University, Ramat Gan 52900, Israel.
Major
Marian
M
Zhang
Xinan
X
Mihalik
Kathleen
K
Rice
Charles M
CM
Perelson
Alan S
AS
Feinstone
Stephen M
SM
Neumann
Avidan U
AU
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D016923:Cell Death; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D006526:Hepatitis C / Q000097:blood / Q000473:pathology / Q000503:physiopathology / Q000821:virology*; D007700:Kinetics; D008954:Models, Biological; D002679:Pan troglodytes; D012367:RNA, Viral / Q000097:blood; D013997:Time Factors; D014771:Virion / Q000502:physiology*; D014779:Virus Replication
D012367:RNA, Viral; D000410:Alanine Transaminase