TABLE 10.16
Viral Defenses against Host RNA Interference
Virus family
Virus
Cell type or organism
Gene product
Effect
Viruses that encode SRS proteins
Nodaviridae
Flock house
Drosophila cell lines,
Protein B2
transgenic plants
Nodamura
Insect cells, mammalian cells
Protein B2
Poxviridae
Vaccinia
Drosophila cell lines
E3L
Inhibit degradation of viral RNAs
Retroviridae
HIV
Human primary T cells
Tat
Bunyaviridae
Tomato spotted wilt
Plants
NSs
LaCrosse
Human 293T cell line
NSs
Viruses that encode miRNAs
Adenoviridae
Adenovirus
Susceptible cells
VAI and VAII
Inhibit DICER
Polyomaviridae
SV-40
Cultured cells
Complements to
Downregulate large T
tumor antigen mRNAs
and small t
Retroviridae
HIV
Cultured cells
miRNAs in env and nef
???
Herpesviridae
Herpes simplex (HHV-1, 2)
Neurons
miR-LAT
Inhibit apoptosis
EpsteinBarr (HHV-4)
Burkitt's lymphoma cell line
5 miRNAs
Maintain latency?
Human cytomegalovirus
Cultured cells
5 expressed miRNAs ???
(HHV-5)
Kaposi's (HHV-8)
???
Several miRNAs
???
Abbreviations: SRS, suppressors of RNA silencing. Data largely from Schütz and Sarnow (2006).
the latently infected neuron alive until such time as the
that could join the plethora of other counterdefense mech-
virus reactivates and enters productive infection. Genes for
anisms these viruses possess. But even viruses with much
miRNAs have been found in a number of other herpes
smaller genomes could potentially encode such small RNAs,
viruses (see Table 10.16) and these miRNAs may also be
as shown by the examples of LaCrosse virus or HIV.
involved in maintaining the latent or persistent infections
established by all herpesviruses.
INTERACTIONS OF VIRUSES WITH THEIR HOSTS
Adenoviruses produce small RNAs of ~160 nucleotides
called VAI and VAII. Transcription is by the host RNA
polymerase III. As described earlier, one function of VAI is
The interaction of viruses with their hosts is intimate and
to bind to PKR and prevent its activation by other dsRNA.
the product of a long period of evolution during which viruses
VAI also interferes with the gene-silencing pathway, as does
coevolved with their hosts. Humans cannot survive without
VAII. They are exported from the nucleus by Exportin5
a functioning immune system to protect them from viruses.
and both VAs can be processed by DICER to VA-miRNAs,
However, this is the result of the long evolutionary history dur-
whose targets are unknown. It has been proposed that adeno-
ing which hosts and viruses adapted to one another, because
virus VAI and VAII, which are produced in large amounts,
viruses in turn cannot survive without their hosts. The exam-
suppress the host RNAi defense by saturating Exportin5,
ple of rabbit myxoma virus demonstrates that the virulence
DICER, and RISC, but there could also be specific repres-
of a virus diminishes if it kills or otherwise incapacitates too
sion of genes by VA-miRNAs.
large a proportion of its hosts too rapidly (see Figs. 7.9 and
SV40 encodes two miRNAs whose activity appears para-
7.10). We can even speculate that the exceptional virulence of
doxical at first glance. They selectively downregulate produc-
the influenza virus responsible for the 1918 pandemic might
tion of SV40 large T and small t antigens. Downregulation of
have been made possible because of active warfare ongoing
these antigens does not result in reduced viral yield, however,
at the time. The virus is so very virulent and incapacitates
but downregulation did lead to reduced activation of cytotoxic
its victims so rapidly that we might expect such a virus to
T cells and helps the virus evade the host immune system.
not persist and spread in the population. But very ill and
Since the field of RNA interference is so new, it is likely
dying soldiers continued to be moved about and the virus
that many of the RNAi-mediated interactions between hosts
could continue to spread, perhaps could even spread more
and viruses have yet to be discovered. The large genomes of
readily, even if it rapidly incapacitated its hosts. On the other
DNA viruses such as the poxviruses and herpesviruses have
hand, the many examples of ways in which viruses modify
lots of room to encode multiple 7080 nucleotide hairpins
the immune and cytokine defenses of the host in order to
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