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viral nonstructural polyprotein, ORF2 (~2 kb) encodes the viral major
capsid protein, and ORF3 encodes a small protein of undefined func-
tion (Fig. 1d). The nonstructural polyprotein ORF1 includes a puta-
tive viral methyltransferase (MeT), a papain-like cysteine protease, an
RNA helicase and a viral RNA-dependent RNA polymerase (RdRp).
The genome contains short 5
-NTRs that have the potential to
fold into conserved stem-loop and hairpin structures. Such secondary
structures are postulated to be important for HEV RNA replication.
The host generates two types of immune responses to control virus
infection. The first is a rapid-onset “innate” response against the virus,
which primarily involves the synthesis of interferons (IFN) and the
stimulation of natural killer lymphocytes. In many cases, the innate
response is sufficient to clear the infection. However, if the infection
proceeds beyond the first few rounds of viral replication, the adaptive
immune response develops antigen-specific antibodies to neutralize
extracellular virions and antigen-specific cytotoxic T cells to clear virus-
infected cells. Another critical host response following viral infection is
the programmed death (apoptosis) of infected cells. To overcome the
host immune responses, viruses use various strategies, many of which
depend on the modulation of signaling pathways that themselves form
the basis of these host responses. Viruses also actively promote the sur-
vival of infected cells by regulating critical signaling pathways. In the
following sections we will discuss known mechanisms and pathways
involved in interferon response, apoptosis and cell survival, and how
hepatitis viruses modulate these to establish and propagate infection.
-and 3
The Interferon System
The interferon (IFN) system is a vital component of the innate immune
response. Interferons are small secretory proteins of the cytokine fam-
ily that help to establish an antiviral state. 12 This system includes two
kinds of cells: those that synthesize interferon in response to viral
infection, and those that include the neighboring bystander cells that
respond to interferon and aid in establishing an antiviral state (Fig. 2).
Type I interferons, IFN
, are produced as a direct response
to viral infection by leukocytes and fibroblasts, respectively. Together,
α
and IFN
β
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