The Evolution of the Major Hepatitis C Genotypes Correlates with Clinical Response to Interferon Therapy

被引:42
作者
Pang, Phillip S. [1 ]
Planet, Paul J. [2 ,3 ]
Glenn, Jeffrey S. [4 ,5 ]
机构
[1] Stanford Univ, Sch Med, Dept Med, Div Infect Dis & Geog Med, Palo Alto, CA 94304 USA
[2] Amer Museum Nat Hist, Dept Pediat, Div Infect Dis, Columbia Presbyterian Med Ctr, New York, NY 10024 USA
[3] Amer Museum Nat Hist, Sackler Inst Comparat Genom, New York, NY 10024 USA
[4] Stanford Univ, Sch Med, Dept Med, Div Gastroenterol & Hepatol, Palo Alto, CA 94304 USA
[5] Palo Alto Vet Adm Med Ctr, Palo Alto, CA USA
来源
PLOS ONE | 2009年 / 4卷 / 08期
关键词
ALPHA-2B PLUS RIBAVIRIN; PHYLOGENETIC TREE SELECTION; NONSTRUCTURAL PROTEIN 5A; PEGINTERFERON ALPHA-2B; VIRUS-INFECTION; VIROLOGICAL RESPONSE; HCV GENOTYPE-2; TREATMENT DURATION; ANTIVIRAL THERAPY; INITIAL TREATMENT;
D O I
10.1371/journal.pone.0006579
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: Patients chronically infected with hepatitis C virus (HCV) require significantly different durations of therapy and achieve substantially different sustained virologic response rates to interferon-based therapies, depending on the HCV genotype with which they are infected. There currently exists no systematic framework that explains these genotype-specific response rates. Since humans are the only known natural hosts for HCV-a virus that is at least hundreds of years old-one possibility is that over the time frame of this relationship, HCV accumulated adaptive mutations that confer increasing resistance to the human immune system. Given that interferon therapy functions by triggering an immune response, we hypothesized that clinical response rates are a reflection of viral evolutionary adaptations to the immune system. Methods and Findings: We have performed the first phylogenetic analysis to include all available full-length HCV genomic sequences (n = 345). This resulted in a new cladogram of HCV. This tree establishes for the first time the relative evolutionary ages of the major HCV genotypes. The outcome data from prospective clinical trials that studied interferon and ribavirin therapy was then mapped onto this new tree. This mapping revealed a correlation between genotype-specific responses to therapy and respective genotype age. This correlation allows us to predict that genotypes 5 and 6, for which there currently are no published prospective trials, will likely have intermediate response rates, similar to genotype 3. Ancestral protein sequence reconstruction was also performed, which identified the HCV proteins E2 and NS5A as potential determinants of genotype-specific clinical outcome. Biochemical studies have independently identified these same two proteins as having genotype-specific abilities to inhibit the innate immune factor double-stranded RNA-dependent protein kinase (PKR). Conclusion: An evolutionary analysis of all available HCV genomes supports the hypothesis that immune selection was a significant driving force in the divergence of the major HCV genotypes and that viral factors that acquired the ability to inhibit the immune response may play a role in determining genotype-specific response rates to interferon therapy.
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页数:12
相关论文
共 107 条
[1]  
Agosti D, 1996, CLADISTICS, V12, P65
[2]   Peginterferon α-2b plus ribavirin compared with interferon α-2b plus ribavirin for initial treatment of chronic hepatitis C in Saudi patients commonly infected with genotype 4 [J].
Alfaleh, FZ ;
Hadad, Q ;
Khuroo, MS ;
Aljumah, A ;
Algamedi, A ;
Alashgar, H ;
Al-Ahdal, MN ;
Mayet, I ;
Khan, MQ ;
Kessie, G .
LIVER INTERNATIONAL, 2004, 24 (06) :568-574
[3]  
[Anonymous], 2002, Gastroenterology, V123, P2082
[4]  
[Anonymous], 2006, THESIS U TEXAS AUSTI
[5]  
[Anonymous], 1991, COMP METHOD EVOLUTIO
[6]   Efficacy of interferon plus ribavirin in the treatment of hepatitis C virus genotype 5 [J].
Antaki, N. ;
Hermes, A. ;
Hadad, M. ;
Ftayeh, M. ;
Antaki, F. ;
Abdo, N. ;
Kebbewar, K. .
JOURNAL OF VIRAL HEPATITIS, 2008, 15 (05) :383-386
[7]   Genome-wide hepatitis C virus amino acid covariance networks can predict response to antiviral therapy in humans [J].
Aurora, Rajeev ;
Donlin, Maureen J. ;
Cannon, Nathan A. ;
Tavis, John E. .
JOURNAL OF CLINICAL INVESTIGATION, 2009, 119 (01) :225-236
[8]   Efficient hepatitis C virus cell culture system: What a difference the host cell makes [J].
Bartenschlager, R ;
Pietschmann, T .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (28) :9739-9740
[9]   Mutations in the E2-PePHD and NS5A region of hepatitis C virus type 1 and the dynamics of hepatitis C viremia decline during interferon alfa treatment [J].
Berg, T ;
Marques, AM ;
Höhne, M ;
Wiedenmann, B ;
Hopf, U ;
Schreier, E .
HEPATOLOGY, 2000, 32 (06) :1386-1395
[10]   Hepatitis C Virus Diversity and Evolution in the Full Open-Reading Frame during Antiviral Therapy [J].
Cannon, Nathan A. ;
Donlin, Maureen J. ;
Fan, Xiaofeng ;
Aurora, Rajeev ;
Tavis, John E. .
PLOS ONE, 2008, 3 (05) :1-12