1. Volume 128, Issue 4, Pages 1056-1066 (April 2005)
Mathematical modeling of primary hepatitis C infection: Noncytolytic clearance and early blockage of virion production 
Harel Dahari, Marian Major, Xinan Zhang, Kathleen Mihalik, Charles M. Rice, Alan S. Perelson, Stephen M. Feinstone, Avidan U. Neumann 
Gastroenterology 
Volume 128, Issue 4, Pages (April 2005)
DOI: /j.gastro
Copyright © 2005 American Gastroenterological Association Terms and Conditions

2. Figure 1
The model was fitted to HCV RNA and ALT data from each chimpanzee during the first 24 weeks postinoculation. The thin lines show a representative fit (T0= 1.87 × 107 hepatocytes/mL; ln(2)/d = 300 days) of the model to the viral load (white squares) and to the ALT data (circles). Black circles indicate the time of seroconversion. Black squares and gray squares indicate that HCV RNA is <40 cp/mL or 200 cp/mL, respectively. The size of the squares is 0.2 log, which is larger than the uncertainty measure of the assay. Note that 2 of the 4 self-limited chimpanzees (C and D) had viral load fluctuations during viral decline, whereas the other 2 animals (A and B) experienced a single viral blip after viral clearance. A better fit in 2 chimpanzees (thick lines in G and H) could be achieved by assuming a reduction in blocking viral production (ϵ) during the rapid viral decrease and ALT flare.
Gastroenterology  , DOI: ( /j.gastro )
Copyright © 2005 American Gastroenterological Association Terms and Conditions

3. Figure 2
Simulation results (HCV RNA, solid line; ALT, circles). (A) The 2 possible mechanisms for biphasic viral increase are blocking de novo infection of target cells (dashed line) and blocking virion production (solid line) starting at time tϵ. The model predicts that only blocking of production gives rise to a transient viral reduction between the 2 phases. This reduction was observed in all chimpanzees with biweekly sampling (Figure 1E, F, and I). (B) Viral plateau together with no increase in ALT are predicted when HCV does not induce faster death of infected cells (δ0 = d). This kinetic profile was observed in 2 chimpanzees (Figure 1F and H). However, if one assumes that target cells are produced only by a constant source (s), then a faster death of infected cells compared with that of noninfected cells (δ0 > d) will not allow for a plateau in viral load. (C) If target cells and infected cells proliferate by a blind homeostasis mechanism, then a viral plateau together with an increase in ALT levels can be found even if HCV induces a somewhat faster death of infected cells (3d > δ0 > d). This kinetic profile was observed in 7 chimpanzees (Figure 1A–E, G, and I). (D) A change at time tkq in the killing rate of infected cells together with cure of noninfected cells (k,q > 0) stimulates the rapid decrease in HCV RNA concomitant with the ALT flare and eventually gives rise to either a lower viral plateau or to viral clearance. (E) Mean susceptible hepatocyte loss due to killing of infected hepatocytes at time tkq is reduced to 25% only when assuming that part of the loss of infected cells is by noncytolytic clearance of intracellular HCV RNA. The mean amount of susceptible hepatocyte loss could be reduced to <10% by assuming a higher ALT secretion due to specific killing of infected cells at time tkq.
Gastroenterology  , DOI: ( /j.gastro )
Copyright © 2005 American Gastroenterological Association Terms and Conditions