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Sahu et al. Neuroimmunol Neuroinflammation 2018;5:2 I http://dx.doi.org/10.20517/2347-8659.2017.43 Page 7 of 14

neuropsychiatric disorders. HCV RNA is detected in CD68+ cells of the CNS (macrophages/microglial)
from 8 cases, suggesting direct HCV neuro invasion . It is hypothesized that presence of lymphatic vessels
[51]
in the brain might be the main pathway allowing infected peripheral blood monocytes to cross the BBB,
and to serve as a precursors of the CNS microglia in addition to TNF-α and IL- 8 secreted by microglial
cells infected with HCV. These two proinflammatory cytokines are toxic to neurons. They mediate a local
inflammatory response and are highly associated with neuropsychiatric disorders. Transcription factor NF-κB
is reported to be involved in cytokine gene expression. Therefore, blocking NF-κB can be a therapeutic
[52]
approach to controlling HCV mediated neuroinflammation .

According to the above study, viral core proteins have been observed to activate microglial cells, astrocytes,
and macrophages of patients infected with HCV. It has been shown that activation of microglial cells
and subsequent diffusion of pro-inflammatory cytokines into the brain occurs as a result of changes in
permeability of the BBB due to induced apoptosis of the brain microvascular endothelial cells in which the
HCV virus replicates .
[53]

Particularly, HCV proteins (core and non- structural) have been demonstrated to be involved in neurotoxicity
in two ways.

(1) Direct exposure of primary human neurons to core proteins of HCV causes neurite retraction, leading to
suppressed neuronal autophagy in the brain. It has been demonstrated that the level of lLC3 is a marker of
autophagosome formation. LC3 is highly expressed in human fetal neurons (HFN) exposed to Gal protein,
while LC-II expression is significantly reduced in HCV core- exposed HFNs. It is suggested that HCV
core proteins have the capability to inhibit LC3-I to LC3-II conversion, thereby reducing autophagosome
formation in HCV core-exposed HFNs. Moreover, Gal-exposed neural cells demonstrated that HCV core
proteins are active at directly at the neuronal membrane, contributing to the death of neurons by modulating
the autophagy pathway .
[54]

(2) HCV proteins activate by both toll-like receptor 2 (TLR2) signaling and extracellular signal-related
kinase (ERK). Prolonged TLR2 mediated activation of ERK has been found to result in neuronal injury/
neurotoxicity.

In addition, a recent study reported that HCV triggers an unfolded protein response (UPR) and
subsequently activates autophagy. Viral infection is often known to cause stress to endoplasmic reticulum
(ER), and UPR (a signaling network) is specifically activated to restore ER homeostasis, refold misfolded
proteins, and trigger the initiation of forming autophagosomes . Consequently, it promotes the replication
[55]
of HCV. However, under circumstances where accumulated unfolded and misfolded proteins in ER lumen
are unresolvable, UPR can lead to apoptosis, resulting in chronic disorders such as neurodegeneration. In
contrast, has also been reported that deficiency of ATG7 can reduce the synthesis of infectious HCV virion
particles without significant effects on the viral protein expressions and/or RNA biosynthesis .
[56]

Moreover, according to the study, interference and subsequently loss of UPR-autophagy by gene silencing
activates the innate immune response. It has been demonstrated that stable silencing of ATG5, or a UPR-
activated transcriptional factor, CCAAT/enhancer binding protein homologous protein (CHOP) could
further upregulate HCV pathogen-associated molecular pattern (PAMP)-triggered interferon-beta (IFNB)
promoter activity and IFNB mRNA level. In addition, attenuated UPR-autophagy also remarkably elevated
the downstream innate immunity pathways to inhibit replication of HCV in a paracrine fashion. Most
importantly, it also demonstrated that a UPR-autophagy suppressing antiviral innate immune response
can occur independently of this virus infection. Thus, interference in the UPR-autophagic pathway by gene
modification exhibits therapeutic potential in suppressing viral replication .
[57]