Scientific Publications by FDA Staff
Gastroenterology 2005 Apr;128(4):1056-66
Mathematical modeling of primary hepatitis C infection: noncytolytic clearance and early blockage of virion production.
Dahari H, Major M, Zhang X, Mihalik K, Rice CM, Perelson AS, Feinstone SM, Neumann AU
Neumann AU, Bar Ilan Univ, Fac Life Sci, IL-52900 Ramat Gan, Israel Bar Ilan Univ, Fac Life Sci, IL-52900 Ramat Gan, Israel Santa Fe Inst, Santa Fe, NM 87501 USA US FDA, Ctr Biol Evaluat & Res, Lab Hepatitis Viruses, Bethesda, MD 20014 USA Rockefeller Univ, Ctr Study Hepatitis C, Lab Virol & Infect Dis, New York, NY 10021 USA Los Alamos Natl Lab, Div Theoret, Los Alamos, NM USA
BACKGROUND & AIMS: 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.
|Category: Journal Article|
|PubMed ID: #15825086|
|Includes FDA Authors from Scientific Area(s): Biologics|
|Entry Created: 2011-10-04||Entry Last Modified: 2012-08-29|