Viruses and RNA interference in mammalian cells

LITERATURE OVERVIEW
1. Intracellular anti-viral responses
Refering to Newton's third law of motion: For every action, there is an equal and
opposite reaction. Even to the viral influence, there is an intracellular reaction in the form
of antiviral responses, such as an interferon (IFN) and RNA interference. These processes
are induced in respond to viral replication and are aimed to control viral replication inside
the infected cell, and through intercellular signaling, in the neighbor cells.
Interferon system
The history of IFN started when, Isaacs and Lindenmann discovered in 1957 that chick cells
infected with influenza virus produced a factor that mediated the transfer of a virus-resistant
state against both homologous and heterologous viruses. Similar findings for vaccinia virus
infection were published by Nagano and Kojima in 1958. These facts have led in future to
the elucidation of the IFN system in exquisite detail. Now this antiviral response with nonspecific
mechanism is known as IFN response (Samuel, 2001).
Interferons are proteins and glycoproteins, inducible cytokines (little peptide information
molecules, that modulate interactions between cells). IFN actions are pleiotropic and affect
many biological processes: antiviral response, regulation of cell growth, cell differentiation
and apoptosis. In general, interferons are divided into two types. Interferons induced by viral
infection - the viral IFNs, which include IFN-α (leukocyte), IFN- β (fibroblast), and IFN- ω,
pertain to type I. Type II - IFN-γ, also known as immune IFN, can be induced by mitogenic
(cause cell transformation or mitosis) or antigenic (cause immune response) stimuli.
Almost all cell types produce type I interferons. Type II IFN-s are produced only by the
cells of immune system.
Production of IFN-s by cells is induced, when abnormally large quantity of dsRNA-s
(double-stranded RNA) is found in a cytoplasm. One of the genes induced by type I IFN-s is
RNA-dependent protein kinase (PKR) gene, which is translated into PKR protein (future
enzyme). However, it is catalytically inactive and requires RNA to be converted in
catalytically active form. The PKR protein changes its conformation, affecting the kinase
catalytic subdomains. Then PKR kinase inhibits initiation of translation by phosphorylating
eIF-2a - the eukaryotic initiation factor of translation. PKR activation and subsequent
phosphorylation of eIF-2a change the translational pattern of the host cell (Figure 1). PKR
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