Caracterización de la evolución del virus de la hepatitis C en la recurrencia postrasplante
Evolution of Hepatitis C virus in patients with post-transplant recurrence\nBackground\nHepatitis C is a massive problem worldwide; it is estimated that there are 170 million people chronically infected. Liver transplantation is the treatment of choice for patients who have reached end-stage cirrhos...
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| Formato: | Tesis de maestría acceptedVersion |
| Lenguaje: | Español |
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Facultad de Farmacia y Bioquímica
2015
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=afamaster&cl=CL1&d=HWA_1124 http://repositoriouba.sisbi.uba.ar/gsdl/collect/afamaster/index/assoc/HWA_1124.dir/1124.PDF |
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| Sumario: | Evolution of Hepatitis C virus in patients with post-transplant recurrence\nBackground\nHepatitis C is a massive problem worldwide; it is estimated that there are 170 million people chronically infected. Liver transplantation is the treatment of choice for patients who have reached end-stage cirrhosis or developed liver cancer. Currently, HCV infection is the most frequent indication for liver transplant.\nRecurrent hepatitis C is virtually universal after liver transplantation; however, an individual patient's clinical course and disease burden are highly variable and difficult to predict. Different viral and host factors that may influence the severity of recurrence have been described; however, the involvement of these factors on the outcome is a controversial issue. Aiim\nTo characterize the implication of liver transplantation in viral evolution of different HCV regions and correlate the evolutionary patterns with the severity of recurrence. Pattiientts and metthods\nThe evolution of NS5B, E2 and Core regions were characterized by sequencing technique followed by phylogenetic analysis in nine HCV chronically infected patients undergoing transplantation (5 of which were HIV co-infected). Thirty-one plasma samples were analyzed (1 to 2 prior to transplantation samples 1 to 3 post transplant samples).\nThe analyzed samples extended over a period of 19,4?10,5 months. HCV recurrence was severe in 5 cases, moderate in the remaining 4 patients and occurred at 4,74?4,87 post transplant months.\nIn two patients viral populations were analyzed by cloning and sequencing of pre and post transplant samples. Resulltts\nHCV genotypes distribution in the cohort was: sg1a 33.3% (n=3), sg1b 44.4% (n=4), sg3a 22.2% (n=2). Substitutions in the NS5b, E2 and Core regions were 2.56 ± 3.05, 15.67 ± 17.25 and 3.71 ± 2.21 substitutions/ patient respectively. Moreover, the synonymous and nonsynonymous substitutions ratio in the NS5B, E2 and Core regions were 0.09 ± 0.25, 0.92 ± 0.83 and 1.17 ± 1.47 respectively.\nIn E2 region a relationship between the substitutions and the time elapsed among samples was observed, consistent with a sequential and cumulative pattern of substitutions.\nPre- and post-transplant viral populations, characterized in two patients, showed a different evolutionary pattern. In one case, no significant differences in diversity and complexity were observed, suggesting that the transplant would not affect viral evolution.\n2\nWhile, in the other case, an effect of "bottleneck", in which post transplantation populations showed less diversity and complexity than that observed in the sample pretransplant, was observed. Diiscussiion\nThe even distribution of genotypes between our cohort and those described in the general population, suggests that this would not be an exclusive and decisive factor that may lead to the need to undergo a transplant.\nThe characterization of viral evolution in the context of liver transplantation provides a fascinating paradigm to explore the complex selection pressures, that underlies the virus-host interaction.\nThe characterized viral regions showed different degrees of nucleotide variability (E2> Core> NS5B), closely related with the biological role that plays in protein biology of the virus.\nThe NS5B region showed a high degree of conservation probably associated with the enzyme protein activity.\nThe E2 region showed an evolutionary pattern of sequential and cumulative substitutions, in tune with the selection and the escape of the immune response, reflecting a constant mechanism of adaptation of the virus to the host.\nFinally, the Core region evolution hinges on a finely poised and complex interplay between the negative selections due to its functional features and the positive selection due to its antigenic properties.\nThe nucleotide sequences of the different regions of each patient, except in one case, grouped in high bootstrap clusters; suggesting that in most of the cases, liver transplantation did not change significantly the quasiespecies balance in such a way that modify the consensus sequence.\nHowever, in E2 region analysis, significantly supported internal groups, where pre and post transplant sequences were separated, were observed in three of seven patients, in which more than 2 samples were analyzed. This result suggests that the transplant might involve selection of a minority population greater adaptation to post-transplant stage.\nThe characterization of viral populations before and after transplantation, performed in two patients, showed different patterns of evolution. In one case, no significant differences in diversity and complexity were observed, suggesting that the transplant would not affect viral evolution. While in the other case an effect of "bottleneck", in which transplantation populations exhibited diversity and complexity lower than that observed in the pre-transplant sample was verified.\n3\nThe implication of liver transplantation in the evolution of HCV is a controversial issue. Some studies suggest that after transplantation, in the absence of effective immune pressure due to immunosuppression, viral population becomes more homogeneous. Pointing out that pretransplant viral diversity is reduced as a result of the "bottleneck" involving transplantation, resulting in a selective pressure of viral variant that best fits to post-transplant stage.\nContrary to the "bottleneck? stage", other studies have described that several HCV lineages are transmitted during the liver transplant, without a significant decrease in viral genetic diversity.\nThe post-transplant recurrence of HCV infection is virtually universal and happens in the vast majority of patients. Nonetheless, the severity of post transplant recurrence is not associated particularly to a specific viral subgenotype and/or HIV coinfection, and seems to be a multifactorial event where in addition to viral factors, host factors as age, ethnicity and immune status of the patient are probably involved. |
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