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Early Evolution of Hepatitis C Virus (HCV) Quasispecies after Liver Transplant for HCV-Related Disease

  1. Dr. Evelyne Schvoerer1,4,5,
  2. Eric Soulier4,
  3. Cathy Royer4,
  4. Anne-Catherine Renaudin1,
  5. Christine Thumann4,
  6. Samira Fafi-Kremer1,4,5,
  7. Nicolas Brignon4,
  8. Stéphane Doridot4,
  9. Nicolas Meyer2,
  10. Patricia Pinson6,
  11. Bernard Ellero3,
  12. Marie-Lorraine Woehl-Jaegle3,
  13. Carole Meyer3,
  14. Philippe Wolf3,
  15. Pierre Zachary1,
  16. Thomas Baumert4,5 and
  17. Françoise Stoll-Keller1,4,5
  1. 1 Laboratoire de Virologie, Strasbourg
  2. 2 Département d’Information Médicale, Hôpital Civil, Strasbourg
  3. 3 Centre de Chirurgie Viscérale et de Transplantation, Hôpital de Hautepierre, Centre Hospitalier Régional Universitaire de Strasbourg, Strasbourg
  4. 4 Unité INSERM 748, Strasbourg
  5. 5 Université Louis Pasteur, Faculté de Médecine, Strasbourg
  6. 6 Centre Hospitalier Universitaire de Bordeaux, Laboratoire de Virologie Hôpital Pellegrin, Bordeaux, France
  1. Reprints or correspondence: Dr. Evelyne Schvoerer Institut de Virologie 3 Rue Koeberlé 67000 Strasbourg France (Evelyne.Schvoerer{at}chru-strasbourg.fr).
 
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Abstract

Background. End-stage liver disease as a result of chronic hepatitis C virus (HCV) infection is the main indication for liver transplant (LT), but allografts are systematically infected with HCV soon after transplant. Viral quasispecies are poorly described during the early posttransplant period.

Methods. For 17 patients who received an LT for HCV disease, plasma viral quasispecies evolution was determined by sequence analysis of hypervariable region 1 of the E2 envelope gene before transplant (BT), after 7 days (D7), and after 1 month (M1). T helper (Th)1/Th2 cytokine levels were determined concomitantly.

Results. HCV quasispecies showed a significant decrease in amino acid diversity at D7 and M1, compared with BT (P < .05). A correlation was observed between low plasma tumor necrosis factor-a levels at D7 and decreased quasispecies amino acid complexity at the same date. Nucleic acid diversity was lower for genotype 1 than for genotype 3 infection (P < .05). The complexity and diversity of amino acids were lower in patients with hepatocellular carcinoma (HCC) BT than in those without HCC (P < .05). Conserved amino acid residues within quasispecies were shared by the whole cohort before and after LT.

Conclusion. Viral structural and/or host immunological features could favor the emergence of fitter HCV strains after LT.

Liver cirrhosis with or without hepatocellular carcinoma (HCC) due to chronic hepatitis C virus (HCV) infection has become the main indication for liver transplant (LT). HCV systematically infects the allograft during the hours after LT. Recurrent hepatitis frequently runs an accelerated course [1]. Unfortunately, antiviral treatment of chronic hepatitis C in LT recipients is limited because of pronounced adverse effects [2]. The high rate of nucleotide mutations during HCV replication in the graft, which allows the generation and selection of fitter variants, as well as modification of the immune response by immunosuppressor treatment, might play a role in outcome of recurrences of HCV infection.

The HCV genome encodes a single polyprotein of 3010–3030 aa that is posttranslationally processed by host and viral proteases into structural and nonstructural proteins. The HCV structural proteins make up the core protein and the 2 envelope glycoproteins E1 and E2, which mediate virus binding and entry [3].

In infected patients, HCV circulates as a mixture of closely related but distinct genomes called quasispecies. The 27-aa-long N-terminal segment of the E2 glycoprotein, termed “hypervariable region 1” (HVR1) exhibits the highest degree of genetic heterogeneity of the whole HCV polyprotein. HVR1 appears to be a major target for neutralizing antibodies and plays a role in binding of the viral envelope to the cell-surface membrane. Thus, the structure and function of the protein domain encoded by this region may play important roles during reinfection of the graft.

Cytokines produced by T lymphocytes and partner cells are suspected to play a pivotal role in HCV recurrence. Schirren et al. [4] observed that a Th1 cytokine profile dominates the intrahepatic and blood-derived immune response in recurrent HCV infection. Two studies showed that patients developing severe cholestatic hepatitis expressed increased levels of Th2 cytokines in the liver [5].

We monitored HVR1 quasispecies evolution in plasma during the early phase after LT. We investigated whether HCV genetic characteristics differed between patients with primary HCC or without HCC before LT (BT) and according to HCV genotype. Concomitantly, the Th1/Th2 cytokine profile was determined in plasma as a reflection of the global immunological status of the patients.

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Materials and Methods

Patients. Seventeen patients undergoing LT for HCV-related cirrhosis were studied (patients P01–P19; samples from P06 and P08 were not available). Twelve patients had received a diagnosis of HCC BT. Inclusion criteria were the presence of HCV RNA in plasma before LT and the provision of informed consent. All patients received immunosuppressive treatment to avoid liver graft rejection (see table 1). Institutional guidelines for human studies were followed.

All patients were observed prospectively by standard clinical and biochemical follow-up (mean duration of follow-up, 20 months). Liver biopsies were performed if necessary, to differentiate HCV-related hepatitis recurrence from graft rejection. HCV recurrent hepatitis was classified by histological examination according to Metavir score, necroinflammatory activity (A) being graded from A0 to A3 and fibrosis (F) from F0 to F4. For the evaluation of Th1/Th2 polarization, HCV-infected patients were studied in comparison with a control group of 9 patients who received LTs because of non-HCV-related disease.

Cloning and sequencing of HVR1 of the HCV E2 coding region. HCV quasispecies were analyzed in plasma samples collected BT and 7 days (D7) and 1 month (M1) after LT. Extraction of total RNA was performed in plasma (QIAmp Viral RNA Mini Kit; Qiagen). The same starting amount of HCV RNA was always used next to a 250–300-ng reverse-transcription polymerase chain reaction (PCR), which was performed on HVR1 using published primers [6] and a Proofstart DNA polymerase (Qiagen). PCR products were cloned by using the TOPO TA Cloning kit (Invitrogen) in accordance with the manufacturer's recommendations (pCR II-TOPO vector, competent Escherichia coli TOP10). Thirteen to 17 clones per sample were sequenced using the 7-Deaza-dGTP kit on the OpenGene DNA Sequencing equipment from Siemens Medical Solutions- Diagnostics.

Quasispecies analysis. The sequences used in the study are available in GenBank (accession numbers EF595687-EF595740). These numbers correspond to 54 clones from 4 representative subjects (P3, P14, P15, and P16). The other sequences are available on request from the corresponding author. Sequences were analyzed by visual inspection of the electrophoregrams (Open-Gene DNA Sequencing System; Siemens Medical Solutions-Diagnostics Software) and were aligned using the Clustal method in MegAlign software (DNAstar). Thirteen to 17 HCV clones were analyzed on each date for the 17 patients. Genetic complexity, defined as the number of viral variants within HCV quasispecies, was evaluated at the nucleotide and amino acid level; complexity was also analyzed by Shannon entropy: Sn = -Sum(pi ln pi)/ ln N , where pi is the frequency of each nucleic acid sequence and N is the total number of sequences analyzed for each patient at each date. Genetic diversity was evaluated using the Hamming score [7], based on the following formula at the nucleotide and amino acid level (means for all the sequences examined by pairs): [1 -(homologous positions/total number of positions)] × 100. The genetic distances were also evaluated according to the Kimura method (using Mega2 software; http://www.megasoftware.net). Synonymous site (dS) nonsynonymous (dN) site values were estimated according to the Nei-Gojobori algorithm (Mega2 software). For phylogenetic trees, the sequences were examined using Clustal W (version 1.83), neighbor-joining Kimura 2-parameter correction, and a neighbor-joining plot.

Routine virological follow-up. Quantitative assessment of plasma HCV RNA was performed using the branched DNA technique (VERSANT HCV RNA 3.0 Assay/bDNA 3.0 Assay; Siemens Medical Solutions-Diagnostics France, sensitivity 615 IU/mL; and Amplicor; Roche, sensitivity 50 IU/mL) (figure 1). HCV genotyping was performed using a lined-probe-based assay targeted to the 5′ uncoding region (LiPA HCV II; Siemens Medical Solutions-Diagnostics).

Figure 1.
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Figure 1.

Hepatitis C virus (HCV) RNA levels in plasma during the first year after transplant

Th1/Th2 bioplex cytokine assay. Concentrations of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12p70, IL-13, granulocyte macrophage colony-stimulating factor, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α were determined using the Bioplex multiplex Human Cytokine Th1/Th2 Assay kit (Bio-Rad) and the Cytokine Reagent kit (Bio-Rad) in accordance with the manufacturer's protocols.

Statistical analysis. All analyses were performed on the whole cohort. The evolution of complexity or diversity of viral quasispecies through time was analyzed using linear mixed models. The impact of several factors on viral HVR1 evolution was assessed: HCV genotype, the presence of HCC before LT, viral load peak BT or 3 months after LT, histological recurrence of HCV-related hepatitis BT or 6 months after LT, and the presence of fibrosis in recurrent hepatitis. Post hoc comparisons between dates were done using the Tukey-Kramer procedure, and an adjusted P < .05 was considered to be significant. Computations were done using SAS software (version 8.0; SAS Institute).

Moreover, subjects were classified into 2 groups depending on whether a decrease in complexity/diversity at D7 after LT was observed (whatever the value of the decrease). The same was done with decrease in plasma cytokine levels (whatever the value of this decrease). Fisher's exact test was used to analyze cross-classifications of the groups mentioned above.

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Results

Patients' characteristics. The mean age of the patients was 53 years (range, 34–69 years); 14 men and 3 women were included. Nine patients were infected with genotype 1b, 3 with genotype 1a, and 5 with genotype 3a. The mean viral load before LT was 5.8 log10 IU/mL (range, 3.7–6.4 log10 IU/mL) (figure 1 and table 1). HCV infection recurred in all 17 patients. No antiviral treatment was given during the first month after LT.

Median follow-up of the patients was 20 months (range, 9–32 months). Satisfactory evolution was defined as HCV infection confirmed by positive results for HCV RNA in serum without detectable clinical or biochemical liver injury. Recurrence of chronic hepatitis C was confirmed by histological examination for 13 patients, with Metavir scores showing mild fibrosis (F1–F2) in 4 of them at the time of the recurrence (table 1) and no fibrosis (F0) in the other patients (n = 9).

Predominant viral variants before and after LT. Apredominant variant, on one date the most frequent strain as well as being ⩾33% of the quasispecies population at the amino acid level, was observed in 13 (76%; P01–P05, P09, P11–P14, and P16–P18) of 17 patients BT. Four patients did not show a predominant variant BT (P07, P10, P15, and P19).

At D7, the same variant remained predominant in 6 (46%; P03, P04, P09, P11, P14, and P18) of these 13 patients. For other 7 LT recipients (P01, P02, P07, P10, P13, P15, and P16), the predominant variant at D7 was present before LT but did not correspond to a variant predominant BT as defined above. In the other 4 LT recipients examined at D7 (P05, P12, P17, and P19), the predominant viral variants were different from the variants before LT. In 1 of these 4 patients (P05), the predominant variant at D7 was completely different from the BT quasispecies and differed from all the other viral quasispecies in the study. Finally, the predominant variant on D7 was maintained as predominant at M1 in 10 patients (P02, P04, P07, P11, P12, and P14–P18), was detected but not predominant in 4 patients (P05, P10, P13, and P19), and was undetected at M1 for the other 3 LT recipients (P01, P03, and P09).

The phylogenetic trees were determined, evidencing some clusters. Four patients were chosen as examples (figure 2).

Figure 2.
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Figure 2.

Phylogenetic trees of 4 patients. P02, P07, and P15 showed a predominant variant emerging at day 7 (D7) after liver transplant (LT) corresponding to a minority before LT (BT) and that was again predominant at 1 month (M1) after LT. P01 is an example showing a complete homogeneous variant emerging at D7 that was present BT even though it was nonpredominant and replaced at M1 by different variants while maintaining a lysine at position 8. Bars indicate genetic distance.

Analysis of HCV quasispecies parameters early after LT. HCV quasispecies were analyzed in plasma BT and at D7 and M1 after LT. A total of 749 clones were sequenced (tables 2 and 3).

Figure 3.
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Figure 3.

Amino acid residues in hypervariable region 1 of E2 in the predominant variants of quasispecies studied for hepatitis C virus-infected liver transplant recipients at 3 dates (before transplant and 7 days and 1 month after). The most conserved residues are indicated in the first line.

Figure 4.
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Figure 4.

Plasma tumor necrosis factor (TNF)-α levels before transplant (BT) and 7 days (D7) and 1 month (M1) after transplant, using the Bioplex multiplex Human Cytokine Th1/Th2 Assay kit.

Table 1.
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Table 1.

Patients' characteristics.

Table 2.
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Table 2.

Analysis of viral quasispecies (complexity and diversity) in the hypervariable region 1 of E2 according to time (before transplant and 7 days and 1 month after).

Table 3.
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Table 3.

Analysis of viral quasispecies (complexity, diversity) in the hypervariable region of E2 according to viral genotype (genotype 3 vs. genotype 1) and to the presence or absence of hepatocellular carcinoma (HCC) before transplant.

HCV amino acid diversity was significantly lower at D7 (6.9) and at M1 (6.4) than at BT (12.1) (P = .04 and P = .02, respectively, corresponding to decreasing values at D7 for 70% of patients and at M1 for 65%). HCV nucleic acid diversity and viral complexity, evaluated at the amino acid and nucleic acid level, also tended to be lower at D7 and M1, compared with BT, albeit nonsignificantly. Shannon entropy and Kimura distance showed the same tendencies. dS -dN analysis of HVR1, according to the Nei-Gojobori algorithm, showed the following results: -0.004 before LT, 0.009 at D7, and 0.007 at M1.

Nucleic acid diversity was significantly lower for HCV genotype 1 (3.7) than for HCV genotype 3 (8.9) (P = .006), with similar results for amino acid diversity and HCV complexity. Shannon entropy and Kimura distance showed the same tendencies: 0.56 for genotype 1 and 0.60 for genotype 3 and 0.05 for genotype 1 and 0.117 for genotype 3, respectively (P = .05). Patients were classified into subgroups showing either a decrease in amino acid complexity at D7 compared with BT (10/17 LT recipients [59%]) or a maintained/increase in complexity at D7. Of the 5 patients who were infected with genotype 3, 4 patients belonged to the first group. dS -dN analysis showed the following results: for patients infected with HCV genotype 3, -0.009 BT, -0.003 at D7, and 0.006 at M1, with a global mean of -0.002; for patients infected with HCV genotype 1, -0.001 BT, 0.014 at D7, and 0.007 at M1, with a global mean of 0.006.

Amino acid complexity and diversity were both lower for patients presenting with HCC BT (i.e., 4.4 and 6.1, respectively; P = .04) than for those without HCC (i.e., 6.7 and 14, respectively; P = .03), as was nucleic acid diversity (i.e., 3.9 vs. 8.4; P = .02). Shannon entropy and Kimura distance showed the same tendencies: 0.51 for patients presenting with HCC and 0.72 for those without HCC (P = .02) and 0.057 for patients presenting with HCC and 0.099 for those without HCC (P = .06), respectively (table 3). The mean model of end-stage liver disease (MELD) score, taking account of liver function, tended to be higher (14.75), corresponding to weaker liver function, for patients with HCC than for patients without (11.42), albeit nonsignificantly.

Early serum alanine aminotransferase (ALT) levels showed a similar development for a large majority of the patients, whatever the evolution of viral quasispecies (data not shown). ALT levels generally increased by up to an average of 5 times the upper limit of normal at D7. ALT levels then decreased and even normalized (n = 12) from M1 and showed weak variations during the first year after LT. Control subjects showed a very similar evolution.

No link could be observed between early or late post-LT peak of HCV viremia or timing of the recurrence of HCV-related hepatitis and quasispecies evolution. However, of the 8 patients with fibrosis (⩾F1) according to Metavir score at M12, 6 showed a decrease in amino acid complexity at D7 compared with BT, whereas only 2 patients with fibrosis showed maintained/increased complexity at D7 (nonsignificant).

Conserved amino acid residues or properties in the HVR1 of E2 gene. Despite high global variability, some positions within HVR1 were invariant or nearly so among all variants, showing threonine, glycine, alanine, phenylalanine, glycine, and glutamine as the most conserved residues at positions 2, 6, 10, 20, 23, and 26, respectively. Globally, basic residues (i.e., arginine, lysine, and histidine) were often observed at positions 3, 11, 14, 25, and 27 (figure 3 and table 4). At positions 4, 5, 8, 10, 13, 17, and 21, uncharged residues were mostly observed (alanine, threonine, valine, and serine). Only P01 showed a lysine at position 8 for the 3 dates. At positions 16, 19, and 20, hydrophobic residues predominated.

Table 4.
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Table 4.

Basic residues in the hypervariable region (HVR) 1 of E2 observed in plasma hepatitis C virus strains from the 17 transplant recipients.

Th1/Th2 cytokines. Production of cytokines was very variable from one patient to another, even though they were all receiving immunosuppressive treatment (figure 4). IL-10 showed a tendency to increase at D7 (vs. BT) and then decrease at M1, even though no significant difference could be shown (data not shown). Interestingly, there was a significant correlation between a decrease in HCV complexity at the amino acid level at D7 (10/17 patients) and a decrease in or continuing undetectable levels of TNF-α at D7, compared with BT (6 and 4 patients, respectively; P = .03). The levels of TNF-α at D7, compared with those BT, were quite variable in the control group (not shown). No link could be observed between both low TNF levels and a decrease in HCV complexity at D7 and liver histological results—the corresponding patients had variable dates of recurrent hepatitis and variable Metavir scores.

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Discussion

A high rate of nucleotide mutation during HCV multiplication in a graft might allow the generation and selection of fitter variants escaping the immune response. In the present study, we observed that HCV quasispecies became more homogeneous during the days after LT. Similar results have been observed by other researchers [8, 9]. In a study of a small cohort of 8 patients that examined HVR1 and HVR2 1.5–2.5 h after graft reperfusion, Hughes et al. [8] showed that, immediately after transplant and before reinfection, specific HCV variants are selected, making viral quasispecies less heterogeneous. Feliu et al. [9] included a number of transplant recipients similar to that of our cohort, and they also observed that, during the first days after LT, HCV quasispecies become more homogeneous: genetic complexity and diversity of HVR1 decreased in 61% and 70% of their patients, respectively. We analyzed structural features of HVR1 because that region has been shown to play a role in cell attachment and to be a target for antibody-mediated neutralization [10]. Despite global variability, amino acid residues at selected sites were conserved in variants of the entire cohort. As observed previously in HCV strains [11], threonine, glycine, alanine, phenylalanine, glycine, and glutamine were more often located at positions 2, 6, 10, 20, 23, and 26 of HVR1, respectively. The physicochemical features of some HVR1 residues were conserved not only within quasispecies but also from BT to M1 after transplant. Indeed, hydrophobic residues such as leucine or phenylalanine were often located at specific sequence positions such as 16, 19, and 20, and basic residues were often observed at positions 3, 11, 14, 25, and 27 (table 4). Interestingly it was shown using retroviral pseudotype particles (HCVpp) harboring HCV envelope glycoproteins that HCV infectivity is increased with the number of basic residues in HVR1 [12]. Furthermore, the presence of a basic residue at position 1 or 8 of HVR1 could have a negative effect on HCVpp infectivity [12]. Applying these findings to results of our study, it is conceivable that the outcome after 24 months of follow-up for patient P01, described here as the only patient with lysine at position 8, could be favored by the presence of this basic residue. Taken together with these findings, the hypothesis that fitter viral populations are selected by the new liver is further supported by the observation that, 1 year after LT, HCV levels are 1-log higher than those BT [1].

HVR1 contains an immunodominant linear B cell epitope recognized by neutralizing antibodies, and variants escaping from antibody-mediated neutralization might be selected. Immunosuppression could also explain the tendency of HCV quasispecies to be more homogeneous. Even though it has to be considered with caution because of the size of the series, we found a correlation between decreased or maintained undetectable levels of TNF-α (P = .03) and a decrease in HCV complexity at the amino acid level at D7. Other authors studying genetic polymorphisms in cytokines found a correlation between low IFN-g production and a fast recurrence of HCV-related hepatitis [13] or an association between TNF-α polymorphisms and hepatic fibrosis [14]. dS -dN analysis in HVR1 showed that the positive constraint on HCV variability before LT was not observed any more at D7 and M1, reflecting low positive pressure such as an immune response in these LT recipients. In the cohort described here, the immunosuppressive treatment used to avoid organ rejection was strong, as revealed by a dramatic decrease in blood dendritic cells and total plasma IL-12 levels at D7 after LT [15]. Other previous studies have shown that immunosuppression itself favors the emergence of homogeneous quasispecies. Interestingly, a decrease in HCV quasispecies variability was observed in HIV/HCV-coinfected patients, in subjects with agammaglobulinemia, and in LT recipients, compared with that in immunocompetent HCV-infected individuals who did not undergo LT [16–18].

The impact of HCV variability on the outcome of liver disease has not yet been clearly defined. In the present study, global amino acid complexity and diversity (obtained for the 3 dates analyzed) were both lower, as was nucleic acid diversity, for patients presenting with primary HCC BT than for those without HCC. Discordant results have been reported regarding a possible relationship between quasispecies and the presence of HCC. The mean MELD score tended to be higher in patients with HCC than in those without HCC. Thus, one can speculate that the weaker liver function observed in patients with HCC in this cohort, accompanied by lower quasispecies complexity and diversity, could be related to each other. Further studies are needed to clarify the role of liver function and viral variability in carcinogenesis [19].

A comparison between genotype 1 or genotype 3 HVR1 quasispecies characteristics was made; to our knowledge, this has never been done before in a transplant setting. It has never been described that global nucleic acid diversity is significantly lower for HCV genotype 1 than for HCV genotype 3 in this context. Interestingly, Silini et al. [18] observed that low quasispecies diversity was associated with recurrent hepatitis only in patients with HLA-DR mismatch and infected with genotype 1b, which has been correlated by some investigators with an unfavorable clinical outcome [20]. The differential pathogenesis of recurrent hepatitis associated with genotype 1 or 3 has to be further investigated. A global positive constraint on HCV variability was more important for HCV genotype 3 and thus was lower for HCV genotype 1, consistent with the higher variability observed in patients in our cohort infected with HCV genotype 3, compared with those infected with HCV genotype 1. Moreover, the role of different cofactors should especially be evaluated (alcohol, sex, and metabolic disease) [21].

Considering the outcome of disease, 6 of 8 patients who developed fibrosis according to Metavir score at M12 showed a decrease in amino acid complexity at D7, whereas only 2 other patients with fibrosis at M12 showed increased amino acid complexity at D7. A possible link between HCV quasi-species variability and severity of HCV reinfection of the liver graft has been suggested in the literature [18, 22–25]. Despite a tendency toward an inverse correlation between quasispecies variability and the outcome of HCV infection, with more homogeneous quasispecies being associated with a severe recurrence, further studies are needed to analyze the relevance of quasispecies evolution and HCV-induced liver disease in the graft.

The origin of HCV reinfecting a transplanted liver and a possible participation of viral strains from nonhepatic sites it is not well known. The extrahepatic replication of HCV has been demonstrated [26–29]. Laskus et al. [26] observed 4 HCV-infected transplant recipients, and, in 3 of them, the posttransplant viral variants resembled those found in pretransplant serum, whereas, in the fourth, viral sequences after LT were identical to those observed in pretransplant peripheral blood mono-nuclear cells. The possible participation of extrahepatic sites deserves further analyses.

In conclusion, our data suggest that structural features of HVR1 of E2 and/or immunological factors related to the host environment could favor the emergence of certain HCV strains after LT that are selected by their ability to infect and that replicate within the transplanted liver and by an escape from antiviral host responses.

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Acknowledgments

We thank Michel Ventura and Marie-Edith Lafon for technical advice and Frederic Schramm for his help in the realization of the figures.

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Footnotes

  • Potential conflicts of interest: none reported.

  • Financial support: Cellule d'Essais Cliniques des Hôpitaux Universitaires de Strasbourg; CHRU Strasbourg (Projet Hospitalier de Recherche Clinique 2864 et Appel à Projets Internes).

  • Received November 27, 2006.
  • Accepted February 21, 2007.
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References

  1. 1.↵
    1. McCaughan GW,
    2. Zekry A
    . Mechanisms of HCV reinfection and allograft damage after liver transplantation. J Hepatol 2004;40:368-74.
    CrossRefMedlineWeb of Science
  2. 2.↵
    1. Terrault NA,
    2. Berenguer M
    . Treating hepatitis C infection in liver transplant recipients. Liver Transpl 2006;12:1192-204.
    CrossRefMedlineWeb of Science
  3. 3.↵
    1. Barth H,
    2. Schnober EK,
    3. Zhang F,
    4. et al
    . Viral and cellular determinants of hepatitis C virus envelope-heparan sulfate interaction. J Virol 2006;80:19579-90.
  4. 4.↵
    1. Schirren CA,
    2. Jung M,
    3. Worzfeld T,
    4. et al
    . Cytokine profile of liver-and blood-derived nonspecific T cells after liver transplantation: T helper cells type 1/0 lymphokines dominate in recurrent hepatitis C virus infection and rejection. Liver Transpl 2000;6:222-8.
    MedlineWeb of Science
  5. 5.↵
    1. Zekry A,
    2. Bishop GA,
    3. Bowen DG,
    4. et al
    . Intrahepatic cytokine profiles associated with posttransplantation hepatitis C virus-related liver injury. Liver Transpl 2002;8:292-301.
    CrossRefMedlineWeb of Science
  6. 6.↵
    1. Neau D,
    2. Jouvencel AC,
    3. Legrand E,
    4. et al
    . Hepatitis C virus genetic variability in 52 human immunodeficiency virus-coinfected patients. J Med Virol 2003;71:41-8.
    CrossRefMedlineWeb of Science
  7. 7.↵
    1. Farci P,
    2. Shimoda A,
    3. Coiana A,
    4. et al
    . The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies. Science 2000;288:339-44.
    Abstract/FREE Full Text
  8. 8.↵
    1. Hughes MG Jr.,
    2. Rudy CK,
    3. Chong TW,
    4. et al
    . E2 quasispecies specificity of hepatitis C virus association with allografts immediately after liver transplantation. Liver Transpl 2004;10:208-16.
    CrossRefMedlineWeb of Science
  9. 9.↵
    1. Feliu A,
    2. Gay E,
    3. Garcia-Retortillo M,
    4. Saiz JC,
    5. Forns X
    . Evolution of hepatitis C virus quasispecies immediately following liver transplantation. Liver Transpl 2004;10:1131-9.
    CrossRefMedlineWeb of Science
  10. 10.↵
    1. Penin F,
    2. ombet C,
    3. ermanidis G,
    4. Frainais PO,
    5. Deleage G,
    6. Pawlotsky JM
    . Conservation of the conformation and positive charges of hepatitis C virus E2 envelope glycoprotein hypervariable region 1 points to a role in cell attachment. J Virol 2001;75:5703-10.
    Abstract/FREE Full Text
  11. 11.↵
    1. Smith DB
    . Evolution of the hypervariable region of hepatitis C virus. J Viral Hepat 1999;6 (Suppl 1):41-6.
    CrossRefMedlineWeb of Science
  12. 12.↵
    1. Callens N,
    2. Ciczora Y,
    3. artosch B,
    4. et al
    . Basic residues in hypervariable region 1 of hepatitis C virus envelope glycoprotein e2 contribute to virus entry. J Virol 2005;79:15331-41.
    Abstract/FREE Full Text
  13. 13.↵
    1. Ben-Ari Z,
    2. Pappo O,
    3. Druzd T,
    4. et al
    . Role of cytokine gene polymorphism and hepatic transforming growth factor β1 expression in recurrent hepatitis C after liver transplantation. Cytokine 2004;27:7-14.
    CrossRefMedlineWeb of Science
  14. 14.↵
    1. usumoto K,
    2. Uto H,
    3. Hayashi K,
    4. et al
    . Interleukin-10 or tumor necrosis factor-a polymorphisms and the natural course of hepatitis C virus infection in a hyperendemic area of Japan. Cytokine 2006;34:24-31.
    CrossRefMedlineWeb of Science
  15. 15.↵
    1. Schvoerer E,
    2. Thumann C,
    3. pohrer S,
    4. et al
    . Early decrease in circulating dendritic cells number after liver transplantation could favor hepatitis C virus recurrence. J Med Virol 2006;78:1070-5.
    CrossRefMedlineWeb of Science
  16. 16.↵
    1. Gaud U,
    2. Langer B,
    3. Petropoulou T,
    4. Thomas HC,
    5. Karayiannis P
    . Changes in hypervariable region 1 of the envelope 2 glycoprotein of hepatitis C virus in children and adults with humoral immune defects. J Med Virol 2003;69:350-6.
    CrossRefMedlineWeb of Science
  17. 17.
    1. Mao Q,
    2. Ray SC,
    3. Laeyendecker O,
    4. et al
    . Human immunodeficiency virus seroconversion and evolution of the hepatitis C virus quasispecies. JVirol 2001;75:3259-67.
    Abstract/FREE Full Text
  18. 18.↵
    1. Silini E,
    2. Belli L,
    3. Brambilla S,
    4. et al
    . Sequence variation in the hyper-variable region 1 of hepatitis C virus and posttransplantation recurrent hepatitis. Liver Transpl 2003;9:1040-7.
    CrossRefMedlineWeb of Science
  19. 19.↵
    1. Pawlotsky JM
    . Hepatitis C virus population dynamics during infection. Curr Top Microbiol Immunol 2006;299:261-84.
    MedlineWeb of Science
  20. 20.↵
    1. Feray C,
    2. Caccamo L,
    3. Alexander GJ,
    4. et al
    . European collaborative study on factors influencing outcome after liver transplantation for hepatitis. Feray C, Caccamo L, Alexander GJ, et al.
  21. 21.↵
    1. Prati D,
    2. Shiffman ML,
    3. Diago M,
    4. et al
    . Viral and metabolic factors influencing alanine aminotransferase activity in patients with chronic hepatitis C. J Hepatol 2006;44:679-85.
    CrossRefMedlineWeb of Science
  22. 22.↵
    1. Sullivan DG,
    2. Wilson JJ,
    3. Carithers RL Jr.,
    4. Perkins JD,
    5. Gretch DR
    . Multigene tracking of hepatitis C virus quasispecies after liver transplantation: correlation of genetic diversification in the envelope region with asymptomatic or mild disease patterns. J Virol 1998;72:10036-43.
    Abstract/FREE Full Text
  23. 23.
    1. Sanchez-Fueyo A,
    2. Gimenez-Barcons M,
    3. Puig-Basagoiti F,
    4. et al
    . Influence of the dynamics of the hypervariable region 1 of hepatitis C virus (HCV) on the histological severity of HCV recurrence after liver transplantation. J Med Virol 2001;65:266-75.
    CrossRefMedlineWeb of Science
  24. 24.
    1. Lyra AC,
    2. Fan X,
    3. Lang DM,
    4. et al
    . Evolution of hepatitis C viral quasispecies after liver transplantation. Gastroenterology 2002;123:1485-93.
    CrossRefMedlineWeb of Science
  25. 25.↵
    1. Doughty AL,
    2. Painter DM,
    3. McCaughan GW
    . Post-transplant quasispecies pattern remains stable over time in patients with recurrent cholestatic hepatitis due to hepatitis C virus. J Hepatol 2000;32:126-34.
    MedlineWeb of Science
  26. 26.↵
    1. Laskus T,
    2. Radkowski M,
    3. Wilkinson J,
    4. Vargas H,
    5. Rakela J
    . The origin of hepatitis C virus reinfecting transplanted livers: serum-derived versus peripheral blood mononuclear cell-derived virus. J Infect Dis 2002;185:417-21.
    Abstract/FREE Full Text
  27. 27.
    1. Goutagny N,
    2. Fatmi A,
    3. De Ledinghen V,
    4. et al
    . Evidence of viral replication in circulating dendritic cells during hepatitis C virus infection. J Infect Dis 2003;187:1951-8.
    Abstract/FREE Full Text
  28. 28.
    1. ucoulombier D,
    2. Roque-Afonso AM,
    3. Di Liberto G,
    4. et al
    . Frequent compartmentalization of hepatitis C virus variants in circulating B cells and monocytes. Hepatology 2004;39:817-25.
    CrossRefMedlineWeb of Science
  29. 29.↵
    1. Pal S,
    2. Sullivan DG,
    3. Kim S,
    4. et al
    . Productive replication of hepatitis C virus in perihepatic lymph nodes in vivo: implications of HCV lymphotropism. Gastroenterology 2006;130:1107-1.
    CrossRefMedlineWeb of Science
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  1. J Infect Dis. (2007) 196 (4): 528-536. doi: 10.1086/519691
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