Intensive temporal mapping of hepatitis C hypervariable region 1 quasispecies provides novel insights into hepatitis C virus evolution in chronic infection
Hepatitis C virus (HCV) is an RNA virus which exists as swarms of closely related viruses known as quasispecies (QS). A number of studies have demonstrated associations between QS hypervariable region 1 (HVR1) characteristics (diversity and complexity) and treatment success. We investigated HCV QS change in chronic infection over intervals of 2–4 weeks in 23 chronically infected individuals to describe the natural history of virus evolution and establish whether HCV QS characteristics could be used to individualize treatment regimens at a molecular level. HVR1 QS diversity, complexity and divergence continue to change in an unpredictable fashion in chronic infection even where there is little phylogenetic change, which is likely to preclude the use of these features in treatment individualization. Our phylogenetic analysis identified no change in the HVR1 QS in 12 subjects, minor change in four subjects and we describe a time-ordered phylogeny for the first time over a period as short as 16 weeks in seven subjects. We identified the existence of multiple subpopulation infections using partitioned analysis of QS and illustrated how subpopulations were sequentially replaced in a number of subjects. We illustrated marked variation in the nucleotide substitution per codon position between patients with sequence change and those without change in the phylogenetic tree. Analysis of codon-specific selection pressures identified a number of codons under purifying selection, suggesting that these code for structurally conserved amino acids. We also identified sections of the HVR1 under positive selection with marked sequence heterogeneity, suggesting that these may be potential epitope-binding sites.
AbbateI.,
Lo IaconoO.,
Di StefanoR.,
CappielloG.,
GirardiE.,
LongoR.,
FerraroD.,
AntonucciG.,
Di MarcoV.,
other authors.
2004; HVR-1 quasispecies modifications occur early and are correlated to initial but not sustained response in HCV-infected patients treated with pegylated- or standard-interferon and ribavirin. J Hepatol 40:831–836 [View Article][PubMed]
BrambillaS.,
BellatiG.,
AstiM.,
LisaA.,
CandussoM.E.,
D'AmicoM.,
GrassiG.,
GiaccaM.,
FranchiniA.,
other authors.
1998; Dynamics of hypervariable region 1 variation in hepatitis C virus infection and correlation with clinical and virological features of liver disease. Hepatology 27:1678–1686 [View Article][PubMed]
CabotB.,
MartellM.,
EstebanJ.I.,
PironM.,
OteroT.,
EstebanR.,
GuardiaJ.,
GómezJ.2001; Longitudinal evaluation of the structure of replicating and circulating hepatitis C virus quasispecies in nonprogressive chronic hepatitis C patients. J Virol 75:12005–12013 doi:10.1128/JVI.75.24.12005-12013.2001 [PubMed][CrossRef]
DoughtyA.L.,
PainterD.M.,
McCaughanG.W.2000; Post-transplant quasispecies pattern remains stable over time in patients with recurrent cholestatic hepatitis due to hepatitis C virus. J Hepatol 32:126–134 [View Article][PubMed]
FanX.,
MaoQ.,
ZhouD.,
LuY.,
XingJ.,
XuY.,
RayS.C.,
Di BisceglieA.M.2009; High diversity of hepatitis C viral quasispecies is associated with early virological response in patients undergoing antiviral therapy. Hepatology 50:1765–1772 [View Article][PubMed]
FarciP.,
ShimodaA.,
CoianaA.,
DiazG.,
PeddisG.,
MelpolderJ.C.,
StrazzeraA.,
ChienD.Y.,
MunozS.J.,
other authors.
2000; The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies. Science 288:339–344 [View Article][PubMed]
FishmanS.L.,
BranchA.D.2009; The quasispecies nature and biological implications of the hepatitis C virus. Infect Genet Evol 9:1158–1167 [View Article][PubMed]
GrahovacB.,
Bingulac-PopovićJ.,
VucelićB.,
HrstićI.,
OstojićR.,
DrazićV.,
BalijaM.,
GrgicevićD.2000; Hypervariable region 1 of hepatitis C virus genome and response to interferon therapy. Clin Chem Lab Med 38:905–910 [View Article][PubMed]
GrayR.R.,
ParkerJ.,
LemeyP.,
SalemiM.,
KatzourakisA.,
PybusO.G.2011; The mode and tempo of hepatitis C virus evolution within and among hosts. BMC Evol Biol 11:131 [View Article][PubMed]
KumagaiN.,
KanekoF.,
TsunematsuS.,
TsuchimotoK.,
TadaS.,
SaitoH.,
HibiT.2007; Complexity of the HVR-1 quasispecies and disease activity in patients with hepatitis C. Eur J Clin Invest 37:566–572 [View Article][PubMed]
LiuL.,
FisherB.E.,
DowdK.A.,
AstemborskiJ.,
CoxA.L.,
RayS.C.2010; Acceleration of hepatitis C virus envelope evolution in humans is consistent with progressive humoral immune selection during the transition from acute to chronic infection. J Virol 84:5067–5077 [View Article][PubMed]
MaoQ.,
RayS.C.,
LaeyendeckerO.,
TicehurstJ.R.,
StrathdeeS.A.,
VlahovD.,
ThomasD.L.2001; Human immunodeficiency virus seroconversion and evolution of the hepatitis C virus quasispecies. J Virol 75:3259–3267 [View Article][PubMed]
McAllisterJ.,
CasinoC.,
DavidsonF.,
PowerJ.,
LawlorE.,
YapP.L.,
SimmondsP.,
SmithD.B.1998; Long-term evolution of the hypervariable region of hepatitis C virus in a common-source-infected cohort. J Virol 72:4893–4905[PubMed]
PalmerB.A.,
MoreauI.,
LevisJ.,
HartyC.,
CrosbieO.,
Kenny-WalshE.,
FanningL.J.2012; Insertion and recombination events at hypervariable region 1 over 9.6 years of hepatitis C virus chronic infection. J Gen Virol 93:2614–2624 [View Article]
PessoaM.G.,
BzowejN.,
BerenguerM.,
PhungY.,
KimM.,
FerrellL.,
HassobaH.,
WrightT.L.1999; Evolution of hepatitis C virus quasispecies in patients with severe cholestatic hepatitis after liver transplantation. Hepatology 30:1513–1520 [View Article][PubMed]
PolyakS.J.,
FaulknerG.,
CarithersR.L.Jr,
CoreyL.,
GretchD.R.1997; Assessment of hepatitis C virus quasispecies heterogeneity by gel shift analysis: correlation with response to interferon therapy. J Infect Dis 175:1101–1107 [View Article][PubMed]
QinH.,
ShireN.J.,
KeenanE.D.,
RousterS.D.,
EysterM.E.,
GoedertJ.J.,
KozielM.J.,
ShermanK.E.2005; Multicenter Hemophilia Cohort Study Group HCV quasispecies evolution: association with progression to end-stage liver disease in hemophiliacs infected with HCV or HCV/HIV. Blood 105:533–541 [View Article][PubMed]
RamachandranS.,
CampoD.S.,
DimitrovaZ.E.,
XiaG.L.,
PurdyM.A.,
KhudyakovY.E.2011; Temporal variations in the hepatitis C virus intrahost population during chronic infection. J Virol 85:6369–6380 [View Article][PubMed]
RayS.C.,
FanningL.,
WangX.-H.,
NetskiD.M.,
Kenny-WalshE.,
ThomasD.L.2005; Divergent and convergent evolution after a common-source outbreak of hepatitis C virus. J Exp Med 201:1753–1759 [View Article][PubMed]
SallieR.2005; Replicative homeostasis II. Influence of polymerase fidelity on RNA virus quasispecies biology: implications for immune recognition, viral autoimmunity and other virus receptor diseases. Virol J 2:70 [View Article][PubMed]
Sánchez-FueyoA.,
Giménez-BarconsM.,
Puig-BasagoitiF.,
RimolaA.,
Sánchez-TapiasJ.M.,
SáizJ.C.,
RodésJ.2001; 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 65:266–275 [View Article][PubMed]
Schmidt-MartinD.,
CrosbieO.,
FanningL.,
Kenny-WalshE.2012; Hepatitis C quasispecies adaptation in the setting of a variable fidelity polymerase. Virus Adapt Treat 4:43–50 [View Article]
SteinhauerD.A.,
DomingoE.,
HollandJ.J.1992; Lack of evidence for proofreading mechanisms associated with an RNA virus polymerase. Gene 122:281–288 [View Article][PubMed]
WangX.H.,
NetskiD.M.,
AstemborskiJ.,
MehtaS.H.,
TorbensonM.S.,
ThomasD.L.,
RayS.C.2007; Progression of fibrosis during chronic hepatitis C is associated with rapid virus evolution. J Virol 81:6513–6522 [View Article][PubMed]
WongJ.B.,
McQuillanG.M.,
McHutchisonJ.G.,
PoynardT.2000; Estimating future hepatitis C morbidity, mortality, and costs in the United States. Am J Public Health 90:1562–1569 [View Article][PubMed]
Intensive temporal mapping of hepatitis C hypervariable region 1 quasispecies provides novel insights into hepatitis C virus evolution in chronic infection