Persistent hepatitis C virus infection in vitro: coevolution of virus and host.
The virological and cellular consequences of persistent hepatitis C virus (HCV) infection have been elusive due to the absence of the requisite experimental systems. Here, we report the establishment and the characteristics of persistent in vitro infection of human hepatoma-derived cells by a recently described HCV genotype 2a infectious molecular clone. Persistent in vitro infection was characterized by the selection of viral variants that displayed accelerated expansion kinetics, higher peak titers, and increased buoyant densities. Sequencing analysis revealed the selection of a single adaptive mutation in the HCV E2 envelope protein that was largely responsible for the variant phenotype. In parallel, as the virus became more aggressive, cells that were resistant to infection emerged, displaying escape mechanisms operative at the level of viral entry, HCV RNA replication, or both. Collectively, these results reveal the existence of coevolutionary events during persistent HCV infection that favor survival of both virus and host.
Zhong
Jin
J
Department of Molecular and Experimental Medicine, SBR-10, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Gastaminza
Pablo
P
Chung
Josan
J
Stamataki
Zania
Z
Isogawa
Masanori
M
Cheng
Guofeng
G
McKeating
Jane A
JA
Chisari
Francis V
FV
D000220:Adaptation, Biological; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000821:virology*; D006801:Humans; D020125:Mutation, Missense; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics; D017422:Sequence Analysis, DNA; D014759:Viral Envelope Proteins; D053586:Virus Internalization; D014779:Virus Replication
D012367:RNA, Viral; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus