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Irshad et al. Hepatoma Res 2018;4:23 I http://dx.doi.org/10.20517/2394-5079.2018.25 Page 7 of 14

proteins which also make a suitable intervention point. Although the exact function of NS4B is not very
clear, it has been found as a good drug target . NS4B also plays an important role in HCV RNA replication
[77]
by forming membranous replication complexes. It has been observed that the C-terminal portion of NS4B is
needed for functional HCV replication complexes . Clemizole has been found as a potent inhibitor of HCV
[78]
RNA replication. This agent blocks the binding of viral RNA to NS4B .
[79]
Apart from viral proteins, some host cell factors also emerged as promising targets for antiviral therapy.
Among host factors contributing to the viral replication cycle, we describe here two main factors that have
been studied in detail, which are cyclophilins and miR-122. Cyclophilins A (CYPA) is the primary host factor
and targeted by immunosuppressive drug cyclosporin A (CsA) [80,81] which inhibits HCV replication in cell
culture . The CYPA-CsA complex also inhibits calcineurin, involved in activation of T cells. Some CYPA
[82]
antagonists have been developed. These compounds are Alisporivir, NIM811 and SCY635. miRNA-122 is
another important host factor that was targeted for the treatment of chronic HCV infection. miRNA-122
stimulates HCV replication by stabilizing HCV RNA [83,84] , translates of the viral genome and enhances
[85]
RNA replication . Naturally, targeting miRNA-122 by antagonist disrupts HCV replication in vitro and
[83]
in vivo [86,87] and therefore becomes an effective target of therapy. miRNA-122 also shows the important role
in hepatocyte lipid homeostasis and it may be taken into account when considering the therapeutic use of
miRNA-122 antagonists.

HCV assembly as target
The experimental studies indicated that antiviral molecules act at different steps of HCV lifecycle. Also
many cellular factors act as candidate targets. The inhibition of α-glucosidases disrupts HCV assembly [88,89] .
The α-glucosidase inhibitors including UT-231B and Celgosivir (MX-3253-a castano-spermine prodrug),
were used as assembly antagonists [90,91] . Identification of diacylglycerol O-acyltransferase-1 (DGAT1), the
factor needed for core protein localization around LDs, indicates that DGAT1 may be a target for therapeutic
intervention . Although diacylglycerol O-acyltransferase-2 (DGAT2) is also involved in LD biogenesis ,
[93]
[92]
HCV targets only DGAT1. Furthermore, DGAT2-generated LDs form normally in DGAT1 inhibitor treated
cells. This shows a limited effect of DGAT1 inhibitors on the cellular functions .
[92]

EFFECT OF VIRAL AND HOST COMPONENTS ON DRUG ACTION
Basline viral load
When baseline viral load is less than 400,000-800,000 IU/mL, the course of treatment may be reduced to 24
weeks in genotype-1/4 patients and to 12-16 weeks in gneotype-2/3 patients. Many studies have shown that
low viral load (HCV-RNA, 600,000-800,000 IU/mL is a good predictor of SVR [94-96] . An increase in viral load
decreases SVR rate.

Viral genotypes
HCV has a total of seven genotypes with more than 50 subtypes and several quasispecies. Genotypes play
very important roles in deciding the host response to anti- viral treatment. Patients infected with genotype-1,
-4, -5, -6 respond worse than those with genotype-2/3 infection. Although, it is not fully established, it is
believed that DAAs have better effect on non-responder genotypes like genotype-1. Using sofosbuvir drug
it has been altered that when it is combined with the SOC regimen, there is a good impact on SVR, both in
genotype-1 and genotype-2/3 patients [97,98] .

Interferon action
Interferons are involved in host natural immune response against various pathogens including HCV .
[99]
Interferon binds with receptors on the target cells and activates signaling pathways like JAK-STAT
pathway. This upregulates IFN-stimulated genes (ISGs) with expression of several types of antiviral effector
protein [100-102] . This has been a basis of using IFN-α as an antiviral agent in chronic HCV infection . However,
[103]