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• W2139054265 abstract "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. 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. Hepatitis C virus (HCV) is a major public health problem, affecting an estimated 170 million people worldwide.1Di Bisceglie A.M. Hepatitis C.Lancet. 1998; 351: 351-355Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar Chronic HCV infection is the main cause of chronic liver disease and cirrhosis leading to liver transplantation or death. Only about 15%–30% of asymptomatic patients2Villano S.A. Vlahov D. Nelson K.E. Cohn S. Thomas D.L. Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection.Hepatology. 1999; 29: 908-914Crossref PubMed Scopus (412) Google Scholar and more than 50% of symptomatic patients3Gerlach J.T. Diepolder H.M. Zachoval R. Gruener N.H. Jung M.C. Ulsenheimer A. Schraut W.W. Schirren C.A. Waechtler M. Backmund M. Pape G.R. Acute hepatitis C high rate of both spontaneous and treatment-induced viral clearance.Gastroenterology. 2003; 125: 80-88Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar with acute hepatitis C spontaneously clear the virus during the early phase of infection, with the remainder progressing to chronic hepatitis. Thus, the first few weeks of interaction between the host’s immune response and the virus probably determine the outcome of the infection. Unlike human immunodeficiency virus and hepatitis B virus (HBV), the onset of HCV infection does not usually cause symptoms. Thus, patients rarely seek medical attention during the acute phase, making it difficult to study early events during infection. However, recent studies with health care workers,4Thimme R. Oldach D. Chang K.M. Steiger C. Ray S.C. Chisari F.V. Determinants of viral clearance and persistence during acute hepatitis C virus infection.J Exp Med. 2001; 19: 1395-1406Crossref Scopus (1011) Google Scholar plasma donors, and blood product recipients5Busch M.P. Insights into the epidemiology, natural history and pathogenesis of hepatitis C virus infection from studies of infected donors and blood product recipients.Transfus Clin Biol. 2001; 8: 200-206Crossref PubMed Scopus (70) Google Scholar have provided insights into early viral and immune events immediately after infection and have shown the existence of a dynamic interplay between virus and host. Moreover, recent clinical results have shown an almost 100% rate of sustained viral response when treatment with interferon (IFN)-α is initiated early (89 days) after infection,6Jaeckel E. Cornberg M. Wedemeyer H. Santantonio T. Mayer J. Zankel M. Pastore G. Dietrich M. Trautwein C. Manns M.P. Treatment of acute hepatitis C with interferon alfa-2b.N Engl J Med. 2001; 345: 1452-1457Crossref PubMed Scopus (760) Google Scholar as compared with about 50% in the chronic phase.7Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales Jr., F.L. Haussinger D. Diago M. Carosi G. Dhumeaux D. Craxi A. Lin A. Hoffman J. Yu J. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5860) Google Scholar, 8Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. Goodman Z.D. Koury K. Ling M. Albrecht J.K. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C a randomised trial.Lancet. 2001; 358: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5872) Google Scholar Thus, it may be clinically important to understand both viral and host dynamics during the acute phase.At present, the chimpanzee is the only infectable animal model available to study the role of HCV-specific immune responses and developing immunity in acute and chronic HCV infection.9Bukh J. Forns X. Emerson S.U. Purcell R.H. Studies of hepatitis C virus in chimpanzees and their importance for vaccine development.Intervirology. 2001; 44: 132-142Crossref PubMed Scopus (52) Google Scholar, 10Esumi M. Rikihisa T. Nishimura S. Goto J. Mizuno K. Zhou Y.H. Shikata T. Experimental vaccine activities of recombinant E1 and E2 glycoproteins and hypervariable region 1 peptides of hepatitis C virus in chimpanzees.Arch Virol. 1999; 144: 973-980Crossref PubMed Scopus (59) Google Scholar, 11Forns X. Payette P.J. Ma X. Satterfield W. Eder G. Mushahwar I.K. Govindarajan S. Davis H.L. Emerson S.U. Purcell R.H. Bukh J. Vaccination of chimpanzees with plasmid DNA encoding the hepatitis C virus (HCV) envelope E2 protein modified the infection after challenge with homologous monoclonal HCV.Hepatology. 2000; 32: 618-625Crossref PubMed Scopus (143) Google Scholar, 12Prince A.M. Brotman B. Lee D.H. Ren L. Moore B.S. Scheffel J.W. Significance of the anti-E2 response in self-limited and chronic hepatitis C virus infections in chimpanzees and in humans.J Infect Dis. 1999; 180: 987-991Crossref PubMed Scopus (37) Google Scholar, 13Sugitani M. Shikata T. Comparison of amino acid sequences in hypervariable region-1 of hepatitis C virus clones between human inocula and the infected chimpanzee sera.Virus Res. 1998; 56: 177-182Crossref PubMed Scopus (21) Google Scholar In a preliminary study, we provided an analysis of HCV kinetics and evolution postinoculation with HCV RNA of a single viral sequence in 2 chimpanzees.14Major M.E. Mihalik K. Fernandez J. Seidman J. Kleiner D. Kolykhalov A.A. Rice C.M. Feinstone S.M. Long-term follow-up of chimpanzees inoculated with the first infectious clone for hepatitis C virus.J Virol. 1999; 73: 3317-3325PubMed Google Scholar Recently, Prince et al15Prince A.M. Pawlotsky J.M. Soulier A. Tobler L. Brotman B. Pfahler W. Lee D.H. Li L. Shata M.T. Hepatitis C virus replication kinetics in chimpanzees with self-limited and chronic infections.J Viral Hepat. 2004; 11: 236-242Crossref PubMed Scopus (18) Google Scholar and we16Major M.E. Dahari H. Mihalik K. Puig M. Rice C.M. Neumann A.U. Feinstone S. Hepatitis C virus kinetics and host responses associated with disease and outcome of infection in chimpanzees.Hepatology. 2004; 39: 1709-1720Crossref PubMed Scopus (126) Google Scholar have shown viral kinetics, quasispecies analysis, and immune responses during acute HCV infection in 38 and 10 naive chimpanzees, respectively. However, to date, the underlying mechanisms that determine the viral replication kinetics and the alanine aminotransferase (ALT) levels in the acute phase are not clear. In this study, we used detailed mathematical modeling to elucidate and quantify virus-host dynamics based on frequent HCV RNA and serum ALT measurements during the acute phase in 10 chimpanzees.16Major M.E. Dahari H. Mihalik K. Puig M. Rice C.M. Neumann A.U. Feinstone S. Hepatitis C virus kinetics and host responses associated with disease and outcome of infection in chimpanzees.Hepatology. 2004; 39: 1709-1720Crossref PubMed Scopus (126) Google Scholar Several models with different possible mechanisms explaining the host effects on viral dynamics were tested. The model that qualitatively best reproduced the empiric data was then used to simultaneously fit the viral and ALT kinetic data, thus allowing us to obtain quantitative estimates of various dynamic parameters for each of the chimpanzees.Materials and methodsChimpanzees and serum analysisThree chimpanzees (1535, 1536, and 1606) were infected by intrahepatic inoculation with RNA transcribed from a full-length complementary DNA clone of genotype 1a HCV isolate H77.17Kolykhalov A.A. Agapov E.V. Blight K.J. Mihalik K. Feinstone S.M. Rice C.M. Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA.Science. 1997; 277: 570-574Crossref PubMed Scopus (621) Google Scholar Seven other chimpanzees were infected intravenously with acute-phase plasma from chimpanzee 1536.14Major M.E. Mihalik K. Fernandez J. Seidman J. Kleiner D. Kolykhalov A.A. Rice C.M. Feinstone S.M. Long-term follow-up of chimpanzees inoculated with the first infectious clone for hepatitis C virus.J Virol. 1999; 73: 3317-3325PubMed Google Scholar Sequence analysis of the HCV in this chimpanzee plasma revealed no detectable variation from the sequence of the complementary DNA clone used to generate the initial RNA inoculum. Viral kinetic data from serum were used as the basis for mathematical modeling, as has been done previously.18Nowak M.A. Lloyd A.L. Vasquez G.M. Wiltrout T.A. Wahl L.M. Bischofberger N. Williams J. Kinter A. Fauci A.S. Hirsch V.M. Lifson J.D. Viral dynamics of primary viremia and antiretroviral therapy in simian immunodeficiency virus infection.J Virol. 1997; 71: 7518-7525PubMed Google Scholar, 19Neumann A.U. Lam N.P. Dahari H. Gretch D.R. Wiley T.E. Layden T.J. Perelson A.S. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy.Science. 1998; 282: 103-107Crossref PubMed Scopus (1889) Google Scholar, 20Perelson A.S. Neumann A.U. Markowitz M. Leonard J.M. Ho D.D. HIV-1 dynamics in vivo virion clearance rate, infected cell life-span, and viral generation time.Science. 1996; 271: 1582-1586Crossref PubMed Scopus (2795) Google Scholar Blood samples were taken weekly for 6 months. Additional blood samples from 3 chimpanzees were taken thrice weekly during the first 2 weeks and twice weekly from week 7 to week 10. HCV RNA levels in the plasma were measured with an in-house real-time (TaqMan) reverse-transcription polymerase chain reaction assay (detection limit, 200 cp/mL) and further analyzed qualitatively by nested reverse-transcription polymerase chain reaction (detection limit, 40 cp/mL).21Puig M. Mihalik K. Yu M. Feinstone S. Major M. Sensitivity and reproducibility of HCV quantitation in chimpanzee sera using TaqMan real-time PCR assay.J Virol Methods. 2002; 105: 253Crossref PubMed Scopus (43) Google Scholar Testing of duplicate samples shows that the coefficient of variation is 2%–4%21Puig M. Mihalik K. Yu M. Feinstone S. Major M. Sensitivity and reproducibility of HCV quantitation in chimpanzee sera using TaqMan real-time PCR assay.J Virol Methods. 2002; 105: 253Crossref PubMed Scopus (43) Google Scholar (data not shown). HCV seroconversion was measured by commercial enzyme immunoassay according to the manufacturer’s instructions (Ortho HCV version 3.0; Ortho Diagnostics, Raritan, NJ).Mathematical modelTo analyze acute HCV infection, we developed a new mathematical model, generalizing our previous model for HCV dynamics under treatment,19Neumann A.U. Lam N.P. Dahari H. Gretch D.R. Wiley T.E. Layden T.J. Perelson A.S. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy.Science. 1998; 282: 103-107Crossref PubMed Scopus (1889) Google Scholar by including additional terms for liver cell proliferation, increased death of infected cells at certain time points, and intracellular clearance of HCV. We also added an equation to describe the kinetics of ALT. The differential equations describing the model are dTdt=s+rT(1−I+TTmax⁡)−dT−βVT+q(t)I(1) dIdt=βVT+rI(1−I+TTmax⁡)−(δ0+κ(t)+q(t))I(2) dVdt=(1−ɛ(t))pI−cV(3) dAdt=ϕ[dT+(δ0+κ(t))I]−σA(4) where T is the concentration of target cells, I is the concentration of productively infected cells, V is the viral load, and A is the ALT concentration. Target cells are assumed to be produced at constant rate s and die with a death rate constant d. De novo infection occurs with rate constant β and once infected cells die due to natural mortality and viral-mediated effects with rate constant δ0. The model also allows for a time-dependent component of the death rate of infected cells, κ(t), due to immune-mediated killing and for noncytolytic clearance of virus from infected cells with rate q(t), where before a certain milestone time, tkq, κ = q = 0. We assume that target cells and infected cells can proliferate with maximum proliferation rate r, under a blind homeostasis process, in which there is no distinction between infected and noninfected cells. Hepatitis C virions are produced by infected cells at average rate p per cell and are cleared with rate constant c. The model also allows for a time-dependent component ϵ(t) of the production of virions from infected cells to change from 0 before the milestone time tϵ to 0 < ϵ < 1 afterward. We assume that ALT is primarily released during hepatocellular necrosis and/or apoptosis22Lutchman G. Hoofnagle J.H. Viral kinetics in hepatitis C.Hepatology. 2003; 37: 1257-1259Crossref PubMed Scopus (19) Google Scholar, 23Lawson J.A. Fisher M.A. Simmons C.A. Farhood A. Jaeschke H. Parenchymal cell apoptosis as a signal for sinusoidal sequestration and transendothelial migration of neutrophils in murine models of endotoxin and Fas-antibody-induced liver injury.Hepatology. 1998; 28: 761-767Crossref PubMed Scopus (152) Google Scholar of both infected and noninfected cells. The amount of ALT generated by a dying cell is represented by ϕ, and ALT spontaneously decays with rate constant σ.Parameter estimationBefore infection, we assume that both ALT and target cells are at steady state, having values A0 and T0, respectively (see estimate below), where T0 = Tmax and V = I = 0. At the time of infection, the viral load is set to V = V0, which is calculated from the infectious dose as follows. Six chimpanzees were infected by plasma from chimpanzee 1536 with 1170 HCV RNA copies, equivalent to an infectious dose of 100 CID50 (after a 1:333 dilution of plasma with an RNA titer of 3.9 × 105 RNA cp/mL and an infectious titer of 104.5 CID50/mL). Chimpanzee 1605 was also infected with serum from chimpanzee 1536 but with only 39 HCV RNA copies (equivalent to an infectious dose of 3.2 CID50). The initial concentration of HCV RNA per milliliter (V0) was calculated using each chimpanzee’s weight based on 13,360 mL of extracellular fluid in a person with a standard weight of 70 kg19Neumann A.U. Lam N.P. Dahari H. Gretch D.R. Wiley T.E. Layden T.J. Perelson A.S. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy.Science. 1998; 282: 103-107Crossref PubMed Scopus (1889) Google Scholar and assuming the same volume/weight ratio for chimpanzees. In the group receiving infectious RNA, we could not assert the infectious dose or initial viral load because H77-RNA molecules, whose infectivity relative to intact virions is unknown, were inoculated into the liver. Thus, a minimal estimate of 0.01 RNA cp/mL was used as the initial viral load, but a maximal estimate (40 RNA cp/mL) did not significantly change the fit.Three parameters (c, T0, and d) have values assigned based on the previous literature. First, we assume that the free virion half-life (ln(2)/c) in chimpanzees is similar to that in chronically infected humans, estimated as 2.7 hours, in our previous study during IFN treatment19Neumann A.U. Lam N.P. Dahari H. Gretch D.R. Wiley T.E. Layden T.J. Perelson A.S. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy.Science. 1998; 282: 103-107Crossref PubMed Scopus (1889) Google Scholar and by others during liver transplantation.24Fukumoto T. Berg T. Ku Y. Bechstein W.O. Knoop M. Lemmens H.P. Lobeck H. Hopf U. Neuhaus P. Viral dynamics of hepatitis C early after orthotopic liver transplantation evidence for rapid turnover of serum virions.Hepatology. 1996; 24: 1351-1354Crossref PubMed Google Scholar, 25Garcia-Retortillo M. Forns X. Feliu A. Moitinho E. Costa J. Navasa M. Rimola A. Rodes J. Hepatitis C virus kinetics during and immediately after liver transplantation.Hepatology. 2002; 35: 680-687Crossref PubMed Scopus (442) Google Scholar We use c = 6 day−1, which corresponds to a half-life of 2.7 hours, and have verified that small changes in c do not modify our results. Second, the number of hepatocytes in a normal human liver was suggested as 2 × 1011.26Sherlock S. Dooley J. Diseases of the liver in humans and biliary system. 11th ed. Blackwell, Oxford2002Google Scholar Because HCV RNA is measured as the number of RNA molecules per milliliter of extracellular fluid, we normalized the initial number of target cells (T0) to obtain a value per milliliter of extracellular fluid for each chimpanzee (as explained above), obtaining a mean of 1.87 × 107 cells/mL. However, due to the uncertain and possibly varying estimate of the number of hepatocytes in a liver, a range of initial hepatocyte count (T0 = 1.87 × 106/mL to 1.87 × 108/mL) was used in the analyses below. Third, the half-life of noninfected hepatocytes (ln(2)/d) was suggested as 300 days,27Macsween R.N.M. Burt A.D. Portmann B.C. Ishak K.G. Scheuer P.J. Anthony P.P. Pathology of the liver.in: Churchill Livingstone, 1987: 21Google Scholar while others have suggested even longer half-lives on a scale of years.28McDonald R.A. Lifespan of liver cells.Arch Intern Med. 1961; 107: 79-87Google Scholar Due to this uncertainty, a range of half-lives was used (50–500 days) rather than a fixed value. In the appendix, we show how we estimate for each chimpanzee the de novo hepatocyte influx rate (s), the HCV production rate (p), and the HCV infection rate (β) by using the calculated slopes of viral increase and the observed viral load plateau of each animal with the above ranges for T0 and d (see Table 1 and Appendix 1).Table 1HCV and ALT Kinetics per Chimpanzee During First 24 Weeks of InfectionChimp no.Infection typeSexFirst-phase virion doubling time (days)Second-phase virion doubling time (days)Viral load at high viral plateau (log cp/mL)Seroconversion time (wk)ALT peak value (IU/L)Half-life of virions during ALT flare (days)Viral load at lower viral plateau (log cp/mL)Outcome of infection1535H77M0.57.76.014.03604.54.9Chronic1536H77M1.116.56.110.03312.44.4Chronic1606H77F0.512.65.39.02971.2NoneNegative1605serumF0.32.76.09.01761.3NoneNegative1629serumM0.43.06.610.02102.34.3Chronic6411serumF0.5106.29.03341.24.9Chronic6412serumF0.57.27.07.07831.04.5NegativeaUndetectable from week 17 until week 28, then back to 4.5 log cp/mL.6455serumF0.36.35.59.02560.8NoneNegative6461serumF0.34.36.26.02102.0NoneNegative6475serumF0.64.65.98.02431.64.0ChronicMean±SD0.5 ± 0.27.5 ± 4.46.1 ± 0.59.0 ± 2.2316 ± 2121.8 ± 1.14.5 ± 0.4a Undetectable from week 17 until week 28, then back to 4.5 log cp/mL. Open table in a new tab The ALT concentration generated by hepatocellular necrosis and/or apoptosis (ϕ) is estimated from the preinfection steady state ALT level as follows: ϕ = (σ × A0)/(d × Tmax), where A0 is the observed level of ALT before infection. Previous and recent reports29Burtis C.A. Ashwood E.R. Tietz Textbook of Clinical Chemistry. 2nd ed. Saunders, Philadelphia, PA1994Google Scholar, 30Zeuzem S. Schmidt J.M. Lee J.H. Ruster B. Roth W.K. Effect of interferon alfa on the dynamics of hepatitis C virus turnover in vivo.Hepatology. 1996; 23: 366-371PubMed Google Scholar, 31Ribeiro R.M. Layden-Almer J. Powers K.A. Layden T.J. Perelson A.S. Dynamics of alanine aminotransferase during hepatitis C virus treatment.Hepatology. 2003; 38: 509-517Crossref PubMed Scopus (47) Google Scholar have suggested ALT half-lives (12.7–100 hours) in extracellular fluid. Because fitting results do not change significantly in this range, we fixed the ALT decay rate at σ = 0.33 day−1, corresponding to a half-life of 50 hours. In addition, because the serum ALT level is the best surrogate marker for hepatocellular necrosis and/or apoptosis,22Lutchman G. Hoofnagle J.H. Viral kinetics in hepatitis C.Hepatology. 2003; 37: 1257-1259Crossref PubMed Scopus (19) Google Scholar, 23Lawson J.A. Fisher M.A. Simmons C.A. Farhood A. Jaeschke H. Parenchymal cell apoptosis as a signal for sinusoidal sequestration and transendothelial migration of neutrophils in murine models of endotoxin and Fas-antibody-induced liver injury.Hepatology. 1998; 28: 761-767Crossref PubMed Scopus (152) Google Scholar we assume that the nonhepatic source of ALT is small compared with the hepatic source and hence is not shown in our model (Equation 4). All other “free” parameters (tϵ, ϵ, tkq, k, q, δ0, and r) were estimated by nonlinear fitting of the observed viral load and ALT kinetics.Nonlinear data fittingFor each chimpanzee, log(V(t)) was fitted to the measured log viral load (cp/mL) and simultaneously log(A(t)/A(t = 0)) was fitted to the measured log ALT enzymatic values (IU/L) normalized to the baseline ALT level. Fitting was done by a nonlinear least squares regression method using Berkeley Madonna software (version 7.0.2; http://www.berkeleymadonna.com). We estimated the “free” parameters in 2 steps as described in Results. Each animal was fitted 5 times with equally separated fixed parameter values for the half-life of noninfected hepatocytes and basal hepatocyte count (ln(2)/d[days], T0[cells/mL]: 50, 1.87 × 106; 50, 1.87 × 108; 500, 1.87 × 106; 500, 1.87 × 108; 300, 1.87 × 107). We excluded fitting results that showed more than a 50% loss of hepatocytes during the ALT flare. The excluded sets of d and T0 are indicated in Table 1.Statistical analysisStatistical analyses were performed using SPSS (SPSS Inc, Chicago, IL). Because HCV RNA and ALT titers were not normally distributed, the data were analyzed by nonparametric methods using Spearman’s formula for rank correlation and Wilcoxon signed rank test and the Mann-Whitney test for paired and unpaired data, respectively. Fisher exact test (2 × 2 tables) and χ2 test (N × N tables) were used to determine the statistical significance of the distribution of categorical variables between groups. Mean results are given with standard deviations.ResultsHCV RNA and ALT kineticsHCV RNA and ALT kinetics can be broken into distinct phases based on the data shown in Table 2 and Figure 1 and described in detail below.Table 2Parameter Estimates of HCV and ALT KineticsChimp no.Viral production rate (p)aSee Appendix 1 for a full description of how these parameters were calculated. (virions/cell/day)Viral infection rate (β)aSee Appendix 1 for a full description of how these parameters were calculated. (10−7mL/virions/day)Starting time of blocking virion production (tϵ) (days)Effectiveness in blocking virion production (ε) (%)Increase death rate of infected cells before ALT flare (δo/d)Starting time of rapid loss of infected cells (tkq) (days)Infected cell half-life during ALT flare ln(2)/(κ+δo)bThe ratio of noncytolytic clearance rate relative to killing rate,q/(κ + δo), is a minimal estimate as mentioned in the Discussion. (days)Noncytolytic virus clearance half-life (ln(2)/q)bThe ratio of noncytolytic clearance rate relative to killing rate,q/(κ + δo), is a minimal estimate as mentioned in the Discussion. (days)Liver cells doubling time (ln(2)/r) (days)15350.5–550.9–1.09.3–12.5961.75–1.83100–10158–10813–136cAs mentioned in Materials and Methods, we have excluded fitting results that yielded more than 50% loss of infected heptocytes. This exclusion has reduced the maximal half-lives of the noncytolytic viral clearance (q) from scales of years to days. The excluded ln(2)/d and To sets (see Materials and Methods) in each animal are as follows: for animals 1535, 1629, 6412, and 6475, the 2 sets with ln(2)/d = 50; for animal 1536, the 2 sets with log(To) = 6; for animal 1606, the ln(2)/d = 500, log(To) = 6 and ln(2)/d = 50, log(To) = 8; for animal 1605, the ln(2)/d = 500, log(To) = 6 and ln(2)/d = 300 − log(To) = 7; for animal 6411, the ln(2)/d = 50, log(To) = 6.58–6315360.9–90.3–0.418.1–24.192–940.97–1.1668–1950–81cAs mentioned in Materials and Methods, we have excluded fitting results that yielded more than 50% loss of infected heptocytes. This exclusion has reduced the maximal half-lives of the noncytolytic viral clearance (q) from scales of years to days. The excluded ln(2)/d and To sets (see Materials and Methods) in each animal are as follows: for animals 1535, 1629, 6412, and 6475, the 2 sets with ln(2)/d = 50; for animal 1536, the 2 sets with log(To) = 6; for animal 1606, the ln(2)/d = 500, log(To) = 6 and ln(2)/d = 50, log(To) = 8; for animal 1605, the ln(2)/d = 500, log(To) = 6 and ln(2)/d = 300 − log(To) = 7; for animal 6411, the ln(2)/d = 50, log(To) = 6.39–8716060.2–203.2–3.46.5–9.8951.3–2.05810–182.8–3.2cAs mentioned in Materials and Methods, we have excluded fitting results that yielded more than 50% loss of infected heptocytes. This exclusion has reduced the maximal half-lives of the noncytolytic viral clearance (q) from scales of years to days. The excluded ln(2)/d and To sets (see Materials and Methods) in each animal are as follows: for animals 1535, 1629, 6412, and 6475, the 2 sets with ln(2)/d = 50; for animal 1536, the 2 sets with log(To) = 6; for animal 1606, the ln(2)/d = 500, log(To) = 6 and ln(2)/d = 50, log(To) = 8; for animal 1605, the ln(2)/d = 500, log(To) = 6 and ln(2)/d = 300 − log(To) = 7; for animal 6411, the ln(2)/d = 50, log(To) = 6.37–28916050.7–711.1–2.52.9–11.594–964.3–11.7492–322–347cAs mentioned in Materials and Methods, we have excluded fitting results that yielded more than 50% loss of infected heptocytes. This exclusion has reduced the maximal half-lives of the noncytolytic viral clearance (q) from scales of years to days. The excluded ln(2)/d and To sets (see Materials and Methods) in each animal are as follows: for animals 1535, 1629, 6412, and 6475, the 2 sets with ln(2)/d = 50; for animal 1536, the 2 sets with log(To) = 6; for animal 1606, the ln(2)/d = 500, log(To) = 6 and ln(2)/d = 50, log(To) = 8; for animal 1605, the ln(2)/d = 500, log(To) = 6 and ln(2)/d = 300 − log(To) = 7; for animal 6411, the ln(2)/d = 50, log(To) = 6.2–716292.6–2160.29–0.317.6–10.592–951.13–1.2258–609–426–11cAs mentioned in Materials and Methods, we have excluded fitting results that yielded more than 50% loss of infected heptocytes. This exclusion has reduced the maximal half-lives of the noncytolytic viral clearance (q) from scales of years to days. The excluded ln(2)/d and To sets (see Materials and Methods) in each animal are as follows: for animals 1535, 1629, 6412, and 6475, the 2 sets with ln(2)/d = 50; for animal 1536, the 2 sets with log(To) = 6; for animal 1606, the ln(2)/d = 500, log(To) = 6 and ln(2)/d = 50, log(To) = 8; for animal 1605, the ln(2)/d = 500, log(To) = 6 and ln(2)/d = 300 − log(To) = 7; for animal 6411, the ln(2)/d = 50, log(To) = 6.30–5864110.5–500.9–9.88.7–11.687–901.4–1.755–578–644–15cAs mentioned in Materials and Methods, we have excluded fitting results that yielded more than 50% loss of infected heptocytes. This exclusion has reduced the maximal half-lives of the noncytolytic viral clearance (q) from scales of years to days. The excluded ln(2)/d and To sets (see Materials and Metho" @default.
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• W2139054265 date "2005-04-01" @default.
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• W2139054265 title "Mathematical modeling of primary hepatitis C infection: Noncytolytic clearance and early blockage of virion production" @default.
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