Coevolution of the Hepatitis C Virus Polyprotein Sites in Patients on Combined Pegylated Interferon and Ribavirin Therapy

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http://jvi.asm.org/cgi/content/abstract/85/7/3649

Journal of Virology, April 2011, p. 3649-3663, Vol. 85, No. 7

0022-538X/11/$012.00+0 doi:10.1128/JVI.02197-10

American Society for Microbiology. .

Coevolution of the Hepatitis C Virus Polyprotein Sites in Patients on Combined

Pegylated Interferon and Ribavirin Therapy ,

Lara,* Guoliang Xia, Mike Purdy, and Yury Khudyakov*

Molecular Epidemiology & Bioinformatics Laboratory, Laboratory Branch, Division

of Viral Hepatitis, Centers for Disease Control and Prevention, 1600 Clifton

Road, Atlanta, Georgia 30333

Received 19 October 2010/ Accepted 7 January 2011

Genotype-specific sensitivity of the hepatitis C virus (HCV) to

interferon-ribavirin (IFN-RBV) combination therapy and reduced HCV response to

IFN-RBV as infection progresses from acute to chronic infection suggest that HCV

genetic factors and intrahost HCV evolution play important roles in therapy

outcomes. HCV polyprotein sequences (n = 40) from 10 patients with unsustainable

response (UR) (breakthrough and relapse) and 10 patients with no response (NR)

following therapy were identified through the Virahep-C study. Bayesian networks

(BNs) were constructed to relate interrelationships among HCV polymorphic sites

to UR/NR outcomes. All models showed an extensive interdependence of HCV sites

and strong connections (P 0.003) to therapy response. Although all HCV proteins

contributed to the networks, the topological properties of sites differed among

proteins. E2 and NS5A together contributed 40% of all sites and 62% of all links

to the polyprotein BN. The NS5A BN and E2 BN predicted UR/NR outcomes with 85%

and 97.5% accuracy, respectively, in 10-fold cross-validation experiments. The

NS5A model constructed using physicochemical properties of only five sites was

shown to predict the UR/NR outcomes with 83.3% accuracy for 6 UR and 12 NR cases

of the HALT-C study. Thus, HCV adaptation to IFN-RBV is a complex trait encoded

in the interrelationships among many sites along the entire HCV polyprotein. E2

and NS5A generate broad epistatic connectivity across the HCV polyprotein and

essentially shape intrahost HCV evolution toward the IFN-RBV resistance. Both

proteins can be used to accurately predict the outcomes of IFN-RBV therapy.

* Corresponding author. Mailing address: Molecular Epidemiology & Bioinformatics

Laboratory, Laboratory Branch, Division of Viral Hepatitis, Centers for Disease

Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333. Phone for J. Lara:

(404) 639-1152. Fax: (404) 639-1563. E-mail: jlara@...

. Phone for Y. Khudyakov: (404) 639-2610. Fax: (404) 639-1563. E-mail:

yek0@...

Published ahead of print on 19 January 2011.

Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, April 2011, p. 3649-3663, Vol. 85, No. 7

0022-538X/11/$012.00+0 doi:10.1128/JVI.02197-10

American Society for Microbiology. .