Book on hepatitis from Page 96 to 105

Book on hepatitis from Page 96 to 105

96  Hepatology 2012
needs NS4A as a cofactor (Failla 1994, Tanji 1995, Bartenschlager 1995, Lin 1995,
Tomei 1996).
HCV RNA replication
The complex process of HCV RNA replication is poorly understood. The key
enzyme for viral RNA replication is NS5B, an RNA-dependent RNA polymerase
(RdRp) of HCV (Behrens 1996). In addition, several cellular as well as viral factors
have been reported to be part of the HCV RNA replication complex. One important
viral factor for the formation of the replication complex appears to be NS4B, which
is able to induce an ER-derived membranous web containing most of the non-structural HCV proteins including NS5B (Egger 2002). This web could serve as the
platform for the next steps of viral RNA replication. The RdRp uses the previously
released genomic positive-stranded HCV RNA as a template for the synthesis of an
intermediate minus-stranded RNA. Recently it has been reported that the cellular
peptidyl-prolyl isomerases cyclophilin A, B and C (Cyp A, Cyp B, and Cyp C)
could stimulate binding of the RdRp to the viral RNA resulting in increased HCV
RNA synthesis (Watashi 2005, Nakagawa 2005, Yang 2008, Heck 2009). However,
these reports are in part inconsistent and further studies are needed in order to
investigate the involvement of cyclophilins in HCV RNA replication.
After the viral polymerase has bound to its template, the NS3 helicase is assumed
to unwind putative secondary structures of the template RNA in order to facilitate
the synthesis of minus-strand RNA (Jin 1995, Kim 1995). In turn, again with the
assistance of the NS3 helicase, the newly synthesized antisense RNA molecule
serves as the template for the synthesis of numerous plus-stranded RNA. The
resulting sense RNA may be used subsequently as genomic RNA for HCV progeny
as well as for polyprotein translation.
Assembly and release
After the viral proteins, glycoproteins, and the genomic HCV RNA have been
synthesized these single components have to be arranged in order to produce
infectious virions. As is the case for all other steps in the HCV lifecycle viral
assembly is a multi-step procedure involving most viral components along with
many cellular factors. Investigation of viral assembly and particle release is still in
its infancy since the development of in vitro models for the production and release
of infectious HCV occurred only recently. Previously, it was reported that core
protein molecules were able to self-assemble in vitro, yielding nucleocapsid-like
particles. More recent findings suggest that viral assembly takes place within the
endoplasmic reticulum (Gastaminza 2008) and that lipid droplets (LD) are involved
in particle formation (Moradpour 1996, Barba 1997, Miyanari 2007, Shavinskaya
2007, Appel 2008). It appears that LD-associated core protein targets viral non-structural proteins and the HCV RNA replication complex including positive- and
negative-stranded RNA from the endoplasmic reticulum to the LD (Miyanari 2007).
Beside the core protein, LD-associated NS5A seems to play a key role in the
formation of infectious viral particles (Appel 2008). Moreover, E2 molecules are
detected in close proximity to LD-associated membranes. Finally, spherical virus-like particles associated with membranes can be seen very close to the LD. Using
HCV Virology  97
specific antibodies the virus-like particles were shown to contain core protein as
well as E2 glycoprotein molecules indicating that these structures may represent
infectious HCV (Miyanari 2007). However, the precise mechanisms for the
formation and release of infectious HCV particles are still unknown.
Model systems for HCV research
For a long time HCV research was limited due to a lack of small animal models and
efficient cell culture systems. The development of the first HCV replicon system
(HCV RNA molecule, or region of HCV RNA, that replicates autonomously from a
single origin of replication) 10 years after the identification of the hepatitis C virus
offered the opportunity to investigate the molecular biology of HCV infection in a
standardized manner (Lohmann 1999).
HCV replicon systems. Using total RNA derived from the explanted liver of an
individual chronically infected with HCV genotype 1b, the entire HCV ORF
sequence was amplified and cloned in two overlapping fragments. The flanking
NTRs were amplified and cloned separately and all fragments were assembled into
a modified full-length sequence. Transfection experiments with in vitro transcripts
derived from the full-length clones failed to yield viral replication. For this reason,
two different subgenomic replicons consisting of the 5’IRES, the neomycin
phosphotransferase gene causing resistance to the antibiotic neomycin, the IRES
derived from the encephalomyocarditis virus (EMCV) and the NS2-3’NTR or NS3-3’NTR sequence, respectively, were generated (Figure 3).
Figure 3. Structure of subgenomic HCV replicons (Lohmann 1999). This figure illustrates
the genetic information of in vitro transcripts used for Huh7 transfection. A) Full-length transcript
derived from the explanted liver of a chronically infected subject. B) Subgenomic replicon
lacking the structural genes and the sequence encoding p7. C) Subgenomic replicon lacking C,
E1, E2, p7, and NS2 genes. neo, neomycin phosphotransferase gene; E-I, IRES of the
encephalomyocarditis virus (EMCV).
98  Hepatology 2012
In vitro transcripts derived from these constructs lacking the genome region
coding for the structural HCV proteins were used to transfect the hepatoma cell line
Huh7 (Lohmann 1999). The transcripts are bicistronic, i.e., the first cistron
containing the HCV IRES enables the translation of the neomycin
phosphotransferase as a tool for efficient selection of successfully transfected cells
and the second cistron containing the EMCV IRES directs translation of the HCV-specific proteins. Only some Huh7 clones can replicate replicon-specific RNA in
titres of approximately 10
8
positive-stranded RNA copies per microgram total RNA.
Moreover, all encoded HCV proteins are detected predominantly in the cytoplasm
of the transfected Huh7 cells. The development of this replicon is a milestone in
HCV research with regard to the investigation of HCV RNA replication and HCV
protein analyses.
More recently, the methodology has been improved in order to achieve
significantly higher replication efficiency. Enhancement of HCV RNA replication
was achieved by the use of replicons harbouring cell culture-adapted point
mutations or deletions within the NS genes (Blight 2000, Lohmann 2001, Krieger
2001). Further development has led to the generation of selectable full-length HCV
replicons, i.e., genomic replicons that also contain genetic information for the
structural proteins Core, E1, and E2 (Pietschmann 2002,  Blight 2002). This
improvement offered the opportunity to investigate the influence of the structural
proteins on HCV replication. Thus it has been possible to analyse the intracellular
localisation of these proteins althoughviral assembly and release has not been
achieved.
Another important milestone was reached when a subgenomic replicon based on
the HCV genotype 2a strain JFH-1 was generated (Kato 2003). This viral strain
derived from a Japanese subject with fulminant hepatitis C (Kato 2001). The
corresponding replicons showed higher RNA replication efficiency than previous
replicons. Moreover, cell lines distinct from Huh7, such as HepG2 or HeLa were
transfected efficiently with transcripts derived from the JFH-1 replicon (Date 2004,
Kato 2005).
HCV pseudotype virus particles (HCVpp).  The generation of retroviral
pseudotypes bearing HCV E1 and E2 glycoproteins (HCVpp) offers the opportunity
to investigate E1-E2-dependent HCVpp entry into Huh7 cells and primary human
hepatocytes (Bartosch 2003a, Hsu 2003, Zhang 2004). In contrast to the HCV
replicons where cells were transfected with HCV-specific synthetic RNA
molecules, this method allows a detailed analysis of the early steps in the HCV life
cycle, e.g., adsorption and viral entry.
Infectious HCV particles in cell culture (HCVcc). Transfection of Huh7 and
‘cured’ Huh7.5 cells with full-length JFH-1 replicons led for the first time to the
production of infectious HCV virions (Zhong 2005, Wakita 2005). The construction
of a chimera with the core NS2 region derived from HCV strain J6 (genotype 2a)
and the remaining sequence derived from JFH-1 improved infectivity. Importantly,
the secreted viral particles are infectious in cell culture (HCVcc) (Wakita 2005,
Zhong 2005, Lindenbach 2005) as well as in chimeric mice with human liver grafts
as well as in chimpanzees (Lindenbach 2006).
An alternative strategy for the production of infectious HCV particles was
developed (Heller 2005): a full-length HCV construct (genotype 1b) was placed
between two ribozymes in a plasmid containing a tetracycline-responsive promoter.
HCV Virology  99
Huh7 cells were transfected with those plasmids, resulting in efficient viral
replication with HCV RNA titres of up to 10
7
copies/ml cell culture supernatant.
The development of cell culture systems that allow the production of infectious
HCV represents a breakthrough for HCV research and it is now possible to
investigate the whole viral life cycle from viral adsorption to virion release. These
studies will help to better understand the mechanisms of HCV pathogenesis and
they should significantly accelerate the development of HCV-specific antiviral
compounds.
Small animal models.  Very recently, substantial progress was achieved in
establishing two mouse models for HCV infection viagenetically humanized mice
(Dorner 2011). In this experiment immunocompetent mice were transduced using
viral vectors containing the genetic information of four human proteins involved in
adsorption and entry of HCV into hepatocytes (CD81, SR-BI, CLDN1, OCLN).
This humanisation procedure enabled the authors to infect the transduced mice with
HCV. Although this mouse model does not enable complete HCV replication in
murine hepatocytes it will be useful to investigate the early steps of HCV infection
in vivo. Moreover, the approach should be suitable for the evaluation of HCV entry
inhibitors and vaccine candidates.
A second group of investigators have chosen another promising strategy for
HCV-specific humanisation of mice. After depleting murine hepatocytes human
CD34(+) hematopoietic stem cells and hepatocyte progenitors were cotransplantated
into transgenic mice leading to efficient engraftment of human leukocytes and
hepatocytes, respectively (Washburn 2011). A portion of the humanised mice
became infectable with primary HCV isolates resulting in low-level HCV RNA in
the murine liver. As a consequence HCV infection induced liver inflammation,
hepatitis, and fibrosis. Furthermore, due to the cotransplantation of CD34(+) human
hematopoietic stem cells, an HCV-specific T cell immune response could be
detected.
Both strategies are promising and have already delivered new insights into viral
replication and the pathogenesis of HCV. However, the methods lack some
important aspects and need to be improved. As soon as genetically humanised mice
that are able to replicate HCV completely are created they can be used for the
investigation of HCV pathogenesis and HCV-specific immune responses. The
Washburn method should be improved in order to achieve higher HCV replication
rates. Moreover, reconstitution of functional human B cells would make this mouse
model suitable to study the important HCV-specific antibody response.
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