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To the Editor:

We read the study by Inoue et al.1 with much interest. The study shed light on hepatitis C virus ribonucleic acid (HCV RNA) kinetics in severe combined immunodeficient (SCID) chimeric mice with human hepatocytes during treatment with pegylated interferon α-2a (PEG-IFN) and/or DEBIO-025, a nonimmunosuppressive cyclophilin inhibitor. Interestingly, Inoue et al.1 showed that mice treated with PEG-IFN alone or in combination with DEBIO-025 had a rapid first phase viral decline (in serum) followed by a slower (genotype 1a) or a flat (genotype 1b) second phase, as has been observed in humans treated with interferon.2 Because interferon-α mainly inhibits viral production,3 we calculated its efficacy, ϵ (Table 1), alone or in combination with DEBIO-025, by digitizing the measured HCV RNA kinetics shown in figures 3B and 4B from Inoue et al.1 As noted by the authors,1 the absence of a second phase decline (observed in genotype 1b) may reflect the lack of an immune response, because these are SCID mice. This would be consistent with the theoretical prediction that the second phase reflects the loss of infected cells.2 The slower second phase (observed in genotype 1a) is interesting because it still occurs in SCID mice.

Table 1. Viral Dynamic Parameters Describing HCV-Infected Chimeric Mice During Therapy
Chimeric mice infected with HCV genotypePercentage of virion production blocked (ϵ =1– Vd4/ V0) [%]2nd phase slope of HCV decay during treatment [log/day]
  1. V0 represents viral load before treatment. Vd4 represents viral load at the transition between the two slope phases in treated mice infected with genotype 1a (day 4) and viral-plateau level (day 4) in treated mice infected with genotype 1b.1 Drug effectiveness was calculated based on equation 4 from Neumann et al.2

1aPEG-IFN: 86%PEG-IFN: 0.05
 PEG-IFN+DEBIO-025: 95%PEG-IFN+DEBIO-025: 0.14
1bPEG-IFN: 86%PEG-IFN: flat
 PEG-IFN+DEBIO-025: 98%PEG-IFN+DEBIO-025: flat

Because HCV itself is not cytopathic,4 one can assume that in SCID mice the death rate of human HCV-infected hepatocytes is approximately equal to the death rate of uninfected human hepatocytes. Thus, the biological interpretation of the rapid second slope phase during PEG-IFN+DEBIO-025 treatment (ϵ = 0.95, second phase slope = 0.14 log/day; Table 1), according to current HCV dynamic models,3 would be that the human hepatocyte half-life in these mice is approximately 5 days. To maintain the observed pretreatment viral steady state in mice,1 the productively-infected hepatocyte population needs to remain constant. Hence, there would need to be proliferation of the transplanted human hepatocytes in mice4 to counterbalance their rapid loss. Further analysis is needed to ascertain this possibility.

Another explanation for the observed biphasic decay of HCV RNA is possible. Biphasic HCV RNA decay has been observed in treated cell cultures that harbor HCV replication.5, 6 Recently, we developed a model for subgenomic HCV replication7 and predicted intracellular biphasic HCV RNA decay.8 We predict (manuscript in preparation) that IFN-α treatment gives a rapid first phase decay of plus-strand HCV RNA (within 24-48 hours) mainly by inhibition of HCV replication. The slower second slope phase, according to the model, represents the rate at which plus-strand RNAs are dissociated from translation complexes and are thus available for rapid degradation and in the context of the fully permissive cell culture system also for packaging and secretion as virions. Therefore, it may be possible that the second slower phase observed in Inoue et al.,1 and in treated patients,2, 3 reflects not only the death/loss of productively-infected cells but also the HCV RNA kinetics within cells. How these kinetics might differ between HCV genotypes 1a and 1b remains to be explored.

References

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  • 1
    Inoue K, Umehara T, Ruegg UT, Yasui F, Watanabe T, Yasuda H, et al. Evaluation of a cyclophilin inhibitor in hepatitis C virus-infected chimeric mice in vivo. HEPATOLOGY 2007; 45: 921928.
  • 2
    Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 1998; 282: 103107.
  • 3
    Perelson AS, Herrmann E, Micol F, Zeuzem S. New kinetic models for the hepatitis C virus. HEPATOLOGY 2005; 42: 749754.
  • 4
    Meuleman P, Libbrecht L, De Vos R, de Hemptinne B, Gevaert K, Vandekerckhove J, et al. Morphological and biochemical characterization of a human liver in a uPA-SCID mouse chimera. HEPATOLOGY 2005; 41: 847856.
  • 5
    Guo JT, Bichko VV, Seeger C. Effect of alpha interferon on the hepatitis C virus replicon. J Virol 2001; 75: 85168523.
  • 6
    Randall G, Grakoui A, Rice CM. Clearance of replicating hepatitis C virus replicon RNAs in cell culture by small interfering RNAs. Proc Natl Acad Sci U S A 2003; 100: 235240.
  • 7
    Dahari H, Ribeiro RM, Rice CM, Perelson AS. Mathematical modeling of subgenomic hepatitis C virus replication in Huh-7 cells. J Virol 2007; 81: 750760.
  • 8
    Dahari H, Ribeiro RM, Perelson AS. Mathematical modeling of intracellular subgenomic HCV RNA kinetics during treatment in Huh-7 cells [Abstract]. HEPATOLOGY 2005; 42(Suppl): 564A.

Harel Dahari*, Alan S. Perelson*, * Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM.