VI01CH06-Sullivan
ARI
ANNUAL
REVIEWS
2 September 2014
6:40
Further
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
Click here for quick links to
Annual Reviews content online,
including:
• Other articles in this volume
• Top cited articles
• Top downloaded articles
• Our comprehensive search
Balance and Stealth:
The Role of Noncoding RNAs
in the Regulation of Virus
Gene Expression
Jennifer E. Cox and Christopher S. Sullivan
Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas 78712;
email: [email protected]
Annu. Rev. Virol. 2014. 1:89–109
Keywords
First published online as a Review in Advance on
June 2, 2014
microRNAs, autoregulation, latency, persistence, reactivation, stress
The Annual Review of Virology is online at
virology.annualreviews.org
Abstract
This article’s doi:
10.1146/annurev-virology-031413-085439
c 2014 by Annual Reviews.
Copyright All rights reserved
In the past two decades, our knowledge of gene regulation has been greatly
expanded by the discovery of microRNAs (miRNAs). miRNAs are small (19–
24 nt) noncoding RNAs (ncRNAs) found in metazoans, plants, and some
viruses. They have been shown to regulate many cellular processes, including differentiation, maintenance of homeostasis, apoptosis, and the immune
response. At present, there are over 300 known viral miRNAs encoded by diverse virus families. One well-characterized function of some viral miRNAs
is the regulation of viral transcripts. Host miRNAs can also regulate viral
gene expression. We propose that viruses take advantage of both host and
viral ncRNA regulation to balance replication and infectious state (for example, latent versus lytic infection). As miRNA regulation can be reversed
upon certain cellular stresses, we hypothesize that ncRNAs can serve viruses
as barometers for cellular stress.
89
VI01CH06-Sullivan
ARI
2 September 2014
6:40
INTRODUCTION
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
Seed sequence:
nucleotides 2–8 of a
mature miRNA;
particularly important
in determining target
interactions
The “grandmother of punk,” American singer-songwriter Patti Smith, once said: “In life may
you proceed with balance and stealth.” Although the context differs, this sentiment accurately
describes the challenges that face viruses that undergo persistent infections. That is, they must have
life cycles with balanced gene expression, maintained through stealthful mechanisms. Persistent
viruses must optimize when, where, and how many virions are produced, while keeping host
cells alive and avoiding the immune response. A major tool viruses use to accomplish this is the
noncoding RNAs. Here we review the current understanding of both host and viral non-proteincoding regulatory RNAs (ncRNAs) in the regulation of virus gene expression.
Over the past decade there has been an exponential increase in our understanding of the role
of ncRNAs in diverse areas of biology. There is an existing or emerging understanding of the
mechanisms of action of several classes of ncRNA, including microRNAs (miRNAs) and long
noncoding RNAs (lncRNAs). miRNAs are small RNAs (typically ∼22 nt) that repress gene expression by directing the RNA-induced silencing complex (RISC) to target mRNA transcripts,
thereby inhibiting translation and/or decreasing the abundance of bound transcripts (1, 2). Unlike
miRNAs, lncRNAs comprise a heterogeneous group of RNAs (typically >200 nt) whose biogenesis and mode of action are poorly defined. Regardless, some lncRNAs have been implicated in
transcriptional and posttranscriptional control of gene expression (3). New classes of ncRNAs and
associated functionalities will continue to emerge with the increased use of high-throughput RNA
sequencing.
Like other fields, virology has been greatly impacted by ncRNAs. Both virus- and host-encoded
ncRNAs contribute to the regulation of virus gene expression and the host response to infection. At
least nine different virus families, spanning much of the Baltimore classification scheme, encode
ncRNAs (4–8). ncRNAs are most prevalent in DNA viruses, but some retroviruses as well as
negative- and positive-strand RNA viruses also give rise to ncRNAs (8, 9; R.P. Kincaid, Y. Chen,
J.E. Cox, A. Rethwilm & C.S. Sullivan, unpublished observations). Although these ncRNAs can be
diverse in terms of sequence, biogenesis, size, and structure, some shared activities are common.
These include evasion of host defenses and regulation of virus gene expression (10). The role of
ncRNAs in host defenses against virus infection has been extensively reviewed (6, 11–15). Here,
we focus on ncRNAs that regulate virus gene expression.
MicroRNAs
miRNAs have been implicated in numerous virus-relevant processes, including the immune response, cell viability, and tumorigenesis (16–18). In the canonical pathway, miRNAs are derived
from a primary transcript containing an approximately 70-nt stem-loop structure that is processed
by the nuclear endonuclease Drosha and then the cytoplasmic endonuclease Dicer to give rise to
the final ∼22-nt effector molecule (19). In general, miRNAs function as rheostats that serve to
dampen gene expression (20). A single miRNA can have hundreds of different targets; conversely,
a single transcript can have numerous docking sites for the same or multiple different miRNAs.
In this manner, a complex web of potential interactions comes together to posttranscriptionally
fine-tune gene expression (6).
miRNAs typically bind to the 3 untranslated region (3 UTR) of their target transcripts
with imperfect complementarity. Commonly, this interaction is mediated in large part by the
seed sequence (nucleotides 2–8), which directly binds to the target transcript via Watson–Crick
base-pairing (21, 22). This results in translational repression, often accompanied by enhanced
turnover of targeted transcripts. Less frequently, miRNAs can bind with perfect complementarity
90
Cox
·
Sullivan
VI01CH06-Sullivan
ARI
2 September 2014
6:40
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
PERSISTENCE AND LATENCY
Following de novo infection, some viruses can establish long-term persistent infections. Often this mode of infection
is cell type–specific. Latency represents a specific subtype of persistent infection, defined as an alternative gene
expression program that does not result in the production of virus (38). A defining characteristic of latency is that it
can be reversed to allow full virus gene expression and production of virions (38). Persistent infections are maintained
through modulation of both viral and cellular gene expression. Currently, there is a limited understanding of the
mechanisms that control the maintenance of persistence and the switch to lytic infection. As many virus-associated
diseases (for example, some cancers) are a consequence of persistent infection or escape from persistence, it is
imperative to better understand the mechanisms of viral persistence. However, many common laboratory models
of virus infection have been selected for the ability of the virus to undergo robust lytic infections and thus may be
inappropriate for modeling persistence. Thus, future work on existing models is warranted, as is the development
of new laboratory models of persistent infection.
(∼22 out of 22 nt) and direct an irreversible cleavage of the target transcript, similar to siRNAs.
This mode of regulation readily occurs in plants but is rarely seen in animals. However, some animal viral miRNAs direct cleavage of their antisense transcripts through this mechanism (23–27).
It is interesting to note that miRNA silencing activity can be attenuated or even inverted in some
circumstances, such as stress (28–33) (discussed below).
In most cases, any target of a miRNA is only subtly regulated by a single miRNA-target
interaction. This suggests that the sum of numerous subtle regulatory events accounts for the
profound biological effects often associated with miRNAs (34). As such, miRNAs can serve to
balance “transcriptional noise” and maintain homeostasis (34–37). Thus, global perturbations of
miRNA activity can be expected to reduce the tolerance of any given cell to various stressors.
To date, over 300 viral miRNAs have been discovered from diverse viruses (6, 38). Most of
these viruses produce long-term, often lifelong, persistent infections (see sidebar, Persistence
and Latency). miRNAs offer several advantages to a virus, including a small genomic footprint
(most miRNAs can be encoded in less than 100 nt of genomic space) and presumed invisibility
to the protein-based adaptive immune response. Although some viral miRNAs serve to block
host defenses (including apoptosis and the adaptive and innate immune responses), an emerging
concept is that many viral miRNAs regulate virus gene expression (10, 39, 40). This is of particular
importance to those viruses that undergo persistent infections, as they need to optimize gene
expression to allow for appropriate induction of the lytic, productive phase of infection. Below,
we present specific examples whereby diverse viruses utilize viral or host miRNAs to control virus
gene expression. For a comprehensive overview of ncRNA regulation of viral transcripts, refer to
Table 1.
VIRAL MicroRNAs
Herpesviruses
Herpesviruses have large, double-stranded DNA genomes, typically greater than 100 kb, that
code for numerous (>65) gene products. Herpesviruses can undergo latent infections in longlived cells such as neurons or immune effector cells (the cell type depends on the infecting virus).
Lytic infection proceeds via a temporally coordinated gene expression cascade from immediate
early through late genes. Lytic infection can occur upon de novo infection or via exit from latency.
www.annualreviews.org • Viral MicroRNAs
91
VI01CH06-Sullivan
ARI
2 September 2014
6:40
Table 1 Summary of viral and host miRNAs known to regulate viral transcripts
Family
Virus(es)
miRNA
Target
Reference(s)
Viral miRNAs
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
Herpesviridae
Epstein–Barr virus (EBV)
Kaposi sarcoma–associated
herpesvirus (KSHV)
Human cytomegalovirus
(HCMV)
Herpes simplex virus 1 and 2
(HSV-1 and -2)
Papillomaviridae
Polyomaviridae
miR-BART2
BALF5a
miR-BART11
EBF1
150
miR-BART3, -BART5,
-BART16, -BART17,
-BART19, -BART20
LMP1
77, 127
miR-BART22
LMP2A
151
miR-BART10
BHRF1
77
miR-BART3, -BART11,
-BART20
EBNA2a
77
miR-K12-9, -K12-7
RTAa
57, 64
miR-K12-10
V-IL-6, V-FLIP,
V-cyclin, V-IRF3,
LANA
57
miR-UL36
UL138
54
miR-UL112
IE1a , UL112/113,
UL114, UL120/121
39, 40, 54
miR-H2
ICP0a
50, 152
26, 77
miR-H3, -H4
ICP34.5
50, 152, 153
Herpes simplex virus 1 (HSV-1)
miR-H6
ICP4
44
Rhesus cytomegalovirus
(RhCMV)
miR-Rh183-1
Rh186
53
Bovine herpesvirus 1 (BoHV-1)
ncRNA 1, 2
bICP0a
154
Gallid herpesvirus 1 (GaHV-1)
miR-I5, -I6
ICP4
155
Marek disease virus (MDV)
miR-M4
UL28, UL32a
156
miR-M7
ICP4
157
miR-M7
ICP27
157
Rhesus lymphocryptovirus
(rLCV)
miR-rL1-17, -rL1-5, -rL1-8,
-rL1-16, -rL1-23
LMP1
127
Bandicoot papillomatosis
carcinomatosis virus type 1
(BPCV1)
miR-B1
Early transcriptsa
89
Bandicoot papillomatosis
carcinomatosis virus type 2
(BPCV2)
miR-B1
Early transcriptsa
89
BK polyomavirus (BKPyV)
miR-B1
Early transcriptsa
24, 90
JC polyomavirus ( JCPyV)
miR-J1
Early
transcriptsa
24
Merkel cell polyomavirus
(MCPyV)
miR-M1
Early transcriptsa
23
Murine polyomavirus (MPyV)
miR-M1
Early transcriptsa
27
Simian agent 12 (SA12)
miR-S1
Early transcriptsa
87
Simian virus 40 (SV40)
miR-S1
Early transcriptsa
25, 88
92
Cox
·
(Continued )
Sullivan
VI01CH06-Sullivan
ARI
2 September 2014
6:40
Table 1 (Continued)
Family
Virus(es)
miRNA
Target
Reference(s)
Viral miRNAs
Baculoviridae
Bombyx mori nuclear
polyhedrosis virus (BmNPV)
miR-8
IE-1
158
Ascoviridae
Heliothis virescens ascovirus
(HvAV)
miR-1
DNA polymerase I
159
Unassigned
Heliothis zea nudivirus 1
(HzNV-1)
pag1-derived miRNAs
hhia
160
Nimaviridae
White spot syndrome virus
(WSSV)
miR-66
wsv094, wsv177
161
miR-68
wsv248, wsv309
161
Adenoviridae
Human adenovirus type 5
(HAdV-5)
miR-214
E1A
162
Hepadnaviridae
Hepatitis B virus (HBV)
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
Host miRNAs
Flaviviridae
Herpesviridae
Pre-S1 region
164
HBsAg
164
Hepatitis C virus (HCV)
miR-122
Binds genome
143
GB virus B (GBV-B)
miR-122
Binds genome
163
Epstein–Barr virus (EBV)
Kaposi sarcoma–associated
herpesvirus (KSHV)
Nimaviridae
miR-210
miR-199a
White spot syndrome virus
(WSSV)
miR-17, -142
LMP1, BHRF1
77
miR-7, -15, -103, -185, -747
EBNA2
77
miR-498, -320d
RTAa
165
miR-142
V-IL-6, V-IRF3
57
let-7
V-FLIP, V-cyclin,
LANA
57
miR-7
wsv477
121
Orthomyxoviridae
H1N1 influenza A virus
let-7c
M1
166
Parvoviridae
Mink enteritis virus (MEV)
miR-181b
NS1
167
Picornaviridae
Enterovirus 71 (EV71)
miR-23b
EV71 VPl
168
miR-296-5p
Viral genome
169
Coxsackievirus B type 3 (CVB3)
Retroviridae
Togaviridae
a
miR-342-5p
2C-coding sequence
170
miR-10a
3D-coding region
171
Avian leucosis virus subgroup J
(ALV-J)
miR-1650
Gag
9
Human immunodeficiency virus
type 1 (HIV-1)
miR-125b, -28, -150, -223,
-382
3 mRNA
118
miR-29a
Nef
117
NEAT1
Replication (increased
Rev-independent
transport)
119
Simian immunodeficiency virus
(SIV)
miR-29a, -29b, -9, -146a
Nef/U3 and R regions
172
Eastern equine encephalitis virus
(EEEV)
miR-142
3 untranslated region
128
Target transcripts that could reinforce persistent infection.
www.annualreviews.org • Viral MicroRNAs
93
VI01CH06-Sullivan
ARI
2 September 2014
Pre-miRNA:
precursor miRNA that
is cleaved by Dicer to
form mature miRNAs
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
AntimiRs: synthetic
oligonucleotides that
inhibit a specific
microRNA
94
6:40
Optimizing the switch from latent to lytic infection is likely crucial to the fitness of the virus and
is controlled by various factors, including chromatin modifications, transcription, and the host
adaptive immune response—all of which can be altered by various stressors (41–43). Recently,
miRNAs have emerged as contributors to latent infection and the regulation of the switch to lytic
infection in diverse herpesviruses (10).
Herpes simplex virus 1 (HSV-1) is the prototypic alphaherpesvirus. HSV-1 is associated with
various diseases including cold sores, genital lesions, and lethal encephalitis. HSV-1 encodes
more than six pre-miRNAs within the latency-associated transcript (LAT) (44, 45). Interestingly,
the miRNAs and LAT are the only readily detectable transcripts during latency. Several HSV-1
miRNAs lie antisense (therefore with perfect complementarity) to the immunomodulatory ICP0
and ICP34.5 transcripts. As would be predicted, mutant viruses lacking HSV-1 miRNAs show
increased expression of both ICP0 and ICP34.5 (44). ICP0 has also been implicated as necessary
for reactivation (46–49). Importantly, infection of cultured Neuro2 cells at a low multiplicity
of infection (MOI) with miRNA-mutant viruses resulted in increased viral replication. This
phenotype was dependent on both MOI and cell type; infection of Neuro2 cells at a higher
MOI or infection of NIH3T3 cells yielded no difference between wild-type and miRNA-mutant
viruses (50). This suggests a possible role for the HSV-1 miRNAs in enforcing latency in vivo,
although such a hypothesis awaits confirmation. Furthermore, the conditional nature of the
increased replication phenotype offers a cautionary note for interpreting those negative studies
in which miRNA mutant viruses show no apparent phenotype (25, 27).
Human cytomegalovirus (HCMV) is a prevalent human betaherpesvirus that is typically asymptomatic in healthy individuals. Infection of the immunocompromised individual or the unborn
fetus can result in life-threatening illnesses and birth defects. Unlike other herpesviruses, the
betaherpesviruses do not express miRNAs from one or a few clusters but rather have numerous distinct miRNA loci (at least 14) dispersed throughout the genome (51). Although multiple
HCMV miRNAs can directly regulate various HCMV transcripts, the functional relevance of most
of these interactions remains unknown (52, 53). The best-studied HCMV miRNA, miR-UL112,
clearly regulates multiple immediate early genes (39, 54). Consequently, ectopic expression of
miR-UL112 can negatively regulate virus replication (54). Grey et al. (39) were among the first
to demonstrate that miR-UL112 can negatively regulate multiple viral transcripts. Furthermore,
engineered mutant viruses (null for either miR-UL112 or one of its direct viral target sites, e.g.,
IE-1) have altered target viral protein levels (40). These studies were performed in fibroblasts
where HCMV undergoes a persistent infection, continuously producing virions. It remains unknown what role HCMV miRNAs might play during latent infection; however, miR-UL112 is
detectable in at least one model of latent infection (55). Furthermore, infection of a mouse model
with a murine cytomegalovirus lacking two miRNAs resulted in less virus production in the salivary glands (56). The phenotype was dependent on both the initial viral titer and the genetic
background of the mouse. It will be interesting to test a similar role for HCMV miRNAs in the
establishment or maintenance of latency.
Kaposi sarcoma–associated herpesvirus (KSHV) is a gammaherpesvirus associated with rare B
cell and endothelial tumors in immunosuppressed patients. KSHV encodes 12 pre-miRNAs that
have a wealth of established host and viral target transcripts (6, 10, 57–61). Although latency is the
typical default pathway for gammaherpesviruses, expression of the immediate early gene product
RTA is sufficient to initiate the lytic replication cycle (62). At least three KSHV miRNAs can negatively regulate RTA expression via direct binding to its 3 UTR (59, 63, 64). Furthermore, several
host targets of KSHV miRNAs have been identified that can affect RTA transcription (65–68).
Whereas inhibition of individual KSHV miRNAs via antimiRs can lead to a decreased or increased
propensity to initiate lytic replication, deletion of 10 of the 12 pre-miRNAs gives rise to viruses with
Cox
·
Sullivan
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
VI01CH06-Sullivan
ARI
2 September 2014
6:40
an increased propensity to undergo lytic activation (64, 67–69). Thus, a model emerges whereby
multiple miRNA-target interactions (of viral and host origin) combine to reinforce latent infection.
In addition to RTA, cross-linking immunoprecipitation (CLIP) studies have revealed several
other viral targets of KSHV miRNAs, including both lytic (V-IL-6, V-FLIP, V-cyclin, V-IRF3)
and latent (LANA) transcripts (57, 59). The benefit to the virus of this regulation remains unknown. However, there are at least two examples of seed conservation between a KSHV miRNA
and two closely related rhesus gammaherpesviruses, termed RFHVM and RRV, which suggests
that some of this regulation is likely evolutionarily conserved (70, 71). Additional viral transcripts
that may be regulated by miRNAs were uncovered by screening a library of KSHV 3 UTR reporters (72). A similar analysis that we conducted revealed an unexpected degree of regulation,
with over 50% of the KSHV 3 UTRs conveying significant negative regulation (73). This implies
a possible global strategy of gene regulation. Interestingly, some of the 3 UTRs convey regulation only in an infectious stage–specific context (that is, only in latent or lytic infection) (73).
Although the mechanisms accounting for this stage-specific regulation are mostly unknown, we
have characterized one such example. This atypical regulation occurs through Drosha cleavage
of pre-miRNAs that are positioned in the 3 UTRs of Kaposin B and K12, as well as the coding
portion of K12 (74). Drosha activity is high in latency, resulting in only a small portion of K12 and
Kaposin B protein-coding transcripts escaping cleavage. However, during lytic infection, Drosha
levels are reduced, with a consequent increase in the transcription of the K12 and Kaposin B
loci. Because a positionally conserved pre-miRNA is found in the 3 UTR of the RFHVM K12
transcript, we predict that this mode of cis regulation is likely evolutionarily conserved (71). We
note, however, that much of the regulatory potential of the KSHV 3 UTRs is independent of cis
or trans effects of the KSHV miRNAs (73). Though well-studied for the RNA viruses, the possible
widespread role of UTRs in DNA virus biology remains an exciting and understudied topic.
Epstein–Barr virus (EBV) is a gammaherpesvirus prevalent in the human population and associated with tumors, especially in immunosuppressed patients. EBV encodes at least 25 pre-miRNAs
derived from one of two separate poly-pre-miRNA clusters (58, 75, 76). In the original description
of EBV miRNAs, due to its antisense location, the transcript encoding the viral DNA polymerase
(BALF5) was identified as a likely target of EBV miR-BART2 (76). This was later functionally
validated by Barth et al. (26). Recently, CLIP strategies on EBV miRNAs have identified numerous host and a few viral target transcripts including LMP1, BHRF1, and EBNA2 (57, 77).
Interestingly, no lytic transcripts (including BALF5) were identified as EBV miRNA targets, but it
remains unclear whether this is due to the low levels of lytic transcripts that “leak” during latency or
whether EBV miRNAs do not target lytic transcripts in a meaningful way (10). However, transfection of an antimiR against miR-BART6 leads to an approximately 2-fold increase in ZTA and RTA
transcripts levels (78). As increased ZTA and RTA could promote lytic activation, these results are
consistent with EBV utilizing miRNAs to optimize the latent/lytic switch. The authors propose
that induction of ZTA and RTA is an indirect result of the global miRNA reduction resulting from
downregulation of Dicer by miR-BART6 (although it remains possible that other targets could account for this phenotype) (78). Despite these data, a mutant EBV defective for miRNA production
did not display increased markers of lytic infection compared with a recombinant virus engineered
to express the full repertoire of EBV miRNAs (79). Thus, it remains unknown whether there exists
a context in which EBV utilizes viral miRNAs to preferentially reinforce latent over lytic infection.
CLIP: cross-linking
immunoprecipitation
RFHVM:
retroperitoneal
fibromatosis
herpesvirus from
pig-tailed macaque;
related to KSHV
RRV: rhesus
rhadinovirus
Polyomaviruses
Polyomaviruses (PyVs) are unrelated to herpesviruses in genome and structure, but they may share
similar challenges in maintaining long-term persistent infections. These small DNA viruses are
www.annualreviews.org • Viral MicroRNAs
95
VI01CH06-Sullivan
ARI
2 September 2014
6:40
prevalent in vertebrates, and at least 12 infect humans (80, 81). Although typically asymptomatic,
in immunosuppressed patients some PyVs have a clear association with rare but serious diseases.
These include Merkel cell carcinoma, progressive multifocal leukoencephalopathy, nephropathy,
organ rejection in transplant patients, and trichodysplasia spinulosa (82–85). The prototypic PyVs
include murine polyomavirus (MPyV) and simian virus 40 (SV40) (86). Both of these emerged
as laboratory models due in part to their selected ability to undergo robust lytic infection in
cultured cells. To date, virus-encoded miRNAs have been identified from at least six different
PyVs (23–25, 27, 87). All are found antisense with perfect complementarity to the early transcripts
that give rise to the multifunctional tumor antigens (T antigens). As would be predicted from
their location, these miRNAs can direct siRNA-like cleavage of the early transcripts (23–25, 27).
Although there are undoubtedly some important host targets, these transcripts differ among the
PyVs, because the seed regions of most PyV miRNAs are not shared. This does not rule out a
possible convergence to regulate similar pathways, as has been suggested for KSHV and EBV
(57). As in the herpesviruses, the genomic positions of the PyV miRNAs are often conserved.
Consequently, the ability to negatively regulate the early transcripts is also conserved. Two lines
of evidence support the importance of miRNA-mediated autoregulation of early gene expression.
First, closely related SV40 isolates can have miRNAs with different seed sequences (and therefore
different host targets) while preserving similar regulatory activity on the early transcripts (88).
Second, the PyV-related bandicoot papillomatosis carcinomatosis viruses (BPCVs) also encode
miRNAs that autoregulate the early T antigen transcripts. However, unlike PyV miRNAs, BPCV
miRNAs are not located antisense to and do not bind with perfect complementarity to the early
transcripts (89). These findings support evolutionary pressure to regulate T antigen transcripts via
miRNAs, as opposed to an alternative model of “tolerating” some degree of negative regulation
as a necessary consequence of the antisense genomic location.
Although the biological relevance of PyV miRNA regulation remains obscure, three studies
implicate a role for the miRNAs in negatively regulating virus copy number (27, 90, 91). Thus,
two non–mutually exclusive models emerge whereby miRNA-mediated autoregulation of the T
antigen transcripts contributes to either (a) lytic infection and/or (b) persistent infection (88). It
has been observed that a substantial fraction of the early transcripts are subjected to miRNAmediated cleavage in lytic models, which suggests a role for autoregulation (25, 88). However, we
note that in some cell culture models, no difference in virus replication for miRNA-mutant viruses
is observed (25, 88). There is also evidence that suggests a role for autoregulation in persistence of
both BK virus and SV40. The BK virus miRNA can limit viral replication in a cultured cell model,
and the SV40 miRNA affects virus copy number during long periods of in vivo infection (25, 90,
91). It is currently unknown whether PyVs maintain long-term persistence via true latency (that
is, via alternative and reversible gene expression profiles). However, as for the herpesviruses, these
data argue that PyV miRNAs play a role in persistent infection. As more is understood about PyV
persistent infection, it will be interesting to determine whether the PyV miRNAs participate in
any hypothetical herpesvirus-like switch to full-on lytic infection.
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
Autoregulation:
regulation of a viral
transcript through a
viral gene product
Retroviruses
Like herpesviruses and polyomaviruses, some retroviruses cause long-term infections and encode
miRNAs. Retroviruses generally possess RNA genomes, but they have unique replication cycles involving integration of a DNA form of the genome (92). In some instances, this integrated provirus
can become transcriptionally silenced. When this occurs in a reactivatable state, it represents a
true latent infection. At least three diverse retroviruses encode miRNAs [bovine leukemia virus
(BLV), avian leucosis virus subgroup J (ALV-J), and some foamy viruses (FVs) (8, 9; R.P. Kincaid,
96
Cox
·
Sullivan
VI01CH06-Sullivan
ARI
2 September 2014
6:40
Y. Chen, J.E. Cox, A. Rethwilm & C.S. Sullivan, unpublished observations)], but some do not
(8, 9, 93). The best characterized retroviral miRNAs include the BLV miRNA B4, which mimics
the oncogenic host miRNA miR-29, and the African green monkey simian foamy virus (SFVagm)
miRNAs S4 and S6, which mimic the host miRNAs miR-155 and miR-132, respectively. All three
of these host miRNAs can be prosurvival and/or immunoevasive. Interestingly, the homologous
genomic region coding for the majority of SFV miRNAs is sometimes lost when the prototypic
virus is cultured ex vivo in cell culture (94–96). These results suggest a possible autoregulatory role
for at least some retroviral miRNAs and raise the possibility that this regulation is advantageous
in maintaining persistent infection in vivo (R.P. Kincaid, Y. Chen, J.E. Cox, A. Rethwilm & C.S.
Sullivan, unpublished observations).
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
ATTENUATED MicroRNA REGULATION DURING STRESS
As multiple virus families utilize miRNAs to control viral gene expression, it is interesting to
note that miRNA-mediated regulation can be attenuated or even reversed during certain forms
of stress. Cellular stressors that can foster reduced miRNA activity include starvation, amino
acid depletion, endoplasmic reticulum stress, oxidative stress, and detection of intracellular or
extracellular pathogen-associated molecular patterns (PAMPs) (29–33). The transition of some
herpesviral and retroviral latent infections into productive virus replication can be promoted by
some of these same stressors (66, 97–103). Thus, it is possible that one mechanism by which
stress induces virus production is by alleviating miRNA-mediated repression of viral and/or host
transcripts. In such a scenario, any miRNA target that is capable of initiating a prolytic feed-forward
loop (for example, RTA in KSHV) could contribute to context-specific virus induction. Although
it awaits validation, such a model implies that viruses may use miRNA-mediated regulation as a
barometer for gauging cellular stress (Figure 1).
HOST MicroRNAs
From a viral perspective, virus-encoded miRNAs seem to offer several advantages, including the
ability to stealthily regulate numerous host and viral transcripts while occupying relatively little
genomic space. Therefore, it is striking that many viruses, especially those with positive- and
negative-strand RNA genomes, do not encode miRNAs. Even some DNA viruses with nuclear
life cycles, including some of the papillomaviruses (PVs), do not encode miRNAs (104, 105). It
is likely that the life cycles of these viruses do not require the fine-tuning regulation provided by
miRNAs, or that they obtain equivalent regulation via alternative strategies. One such strategy
used by diverse viruses is to take advantage of host miRNAs. As discussed below, host miRNA–
mediated regulation of virus gene expression can lead to consequential biological effects.
The PVs are small viruses with circular, double-stranded DNA; they are the causative agents
of benign warts and several human cancers (106). Two reports (107, 108) claim that several
alphapapillomavirus types (6, 16, 18, 38, 45, 68) encode miRNAs. However, these reports have
not been independently verified and suffer from a lower level of experimental verification than
is currently the norm for the field. Thus, it is not widely accepted that PVs encode miRNAs.
What is clear is that at least one PV, human papillomavirus 31 (HPV-31), does not encode its own
miRNAs (104, 105).
PVs can cause long-term persistent infections, whereby the genome is maintained as an
episome in undifferentiated keratinocytes (109). Only upon cellular differentiation is the full
repertoire of viral proteins expressed (109). Gunasekharan & Laimins (105) found in a raft
culture model of keratinocyte differentiation that 93 host miRNAs were differentially expressed
in the presence of the HPV-31 genome. One of these miRNAs, miR-145, directly targeted the
www.annualreviews.org • Viral MicroRNAs
97
VI01CH06-Sullivan
ARI
2 September 2014
6:40
a
b
Latency: low stress
Lytic: high stress
Stress
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
RISC
RTA
ZTA
T antigens
IE1
ICP0
UL28
UL32
hhi1
RISC
gets
t tar
Hos
RTA
ZTA
T antigens
IE1
ICP0
UL28
UL32
hhi1
gets
t tar
Hos
NA
miR vity
i
t
ac
Prolytic
transcripts
miRNA
activity
ytic
Prol cripts
s
n
a
tr
Figure 1
Hypothetical model: MicroRNAs function as a “barometer” of stress. Note that the figure represents a schematic version of infection
rather than the life cycle of any specific virus. (a) During persistence or latency, miRNAs restrict expression of viral and/or host
transcripts that promote lytic infection (e.g., Kaposi sarcoma–associated herpesvirus RTA, Epstein–Barr virus ZTA, polyomaviral T
antigens). In this regard, miRNAs serve to balance prolytic transcripts and to maintain and reinforce persistence or latency. (b) Under
stress conditions, miRNA suppressive activity is reduced, thus allowing increased expression of prolytic transcripts. Therefore, under
stress conditions, alleviation of miRNA suppression can contribute to initiating or increasing lytic infection. Abbreviation: RISC,
RNA-induced silencing complex.
polycistronic early viral transcripts that can give rise to multiple different viral proteins (105).
This regulation has functional relevance, as forced expression of miR-145 results in reduced viral
genome amplification upon cell differentiation (105). In this way, HPV seems to manipulate host
miR-145 levels to restrict genome amplification in undifferentiated cells, while allowing for full
virus gene expression in differentiated cells. Thus, HPVs may use host miRNAs to the same ends
as the PyVs and other viruses use autoregulatory viral miRNAs.
In addition to viruses altering host miRNAs to regulate virus gene expression, some viruses
have altered tissue distribution due to preexisting differences in host miRNAs. The North American eastern equine encephalitis virus (EEEV) is an alphavirus that can be transmitted to humans
via mosquito vectors (110). Although the case mortality rate is high, humans are generally considered to be a dead-end host; birds are the major vertebrate hosts of this arbovirus (111). There
are direct target sites for the host miRNA miR-142-3p in the 3 UTR of EEEV (112). Through
the use of overexpression and inhibition strategies, it was demonstrated that miR-142 restricts
EEEV replication. Interestingly, miR-142 expression is abundant only in hematopoietic cells,
suggesting that this mechanism accounts for the lack of replication of EEEV in certain cell types
such as macrophages and dendritic cells (112). In a mouse model, a mutant virus that is resistant
to miR-142 regulation restores replication in macrophages (112). This gives rise to increased
98
Cox
·
Sullivan
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
VI01CH06-Sullivan
ARI
2 September 2014
6:40
interferon-α/β serum levels, and the virus is consequently less virulent (112). Even though
mosquitoes do not express miR-142, the genomic region surrounding the docking sites for miR142 is important for replication in the mosquito. The authors interpret this as evidence that this
region of the UTR has redundant functions in the arbovector, and they suggest that this phenomenon may contribute to the positive selective pressure required to maintain these miRNA
target sites (112). An alternative, non–mutually exclusive model is that miR-142-mediated regulation in the avian hosts could be advantageous to the virus, perhaps by allowing evasion of the innate
immune response while somehow still permitting high enough levels of viremia. Thus, viruses may
use miRNAs not only to coordinate with the differentiation and stress status of infected cells but
also to limit replication in particular tissues.
In the past 10 years, there has been an ongoing debate involving miRNA regulation of HIV.
In the midst of the controversy are contradicting reports that HIV encodes several miRNAs (60,
93, 113–116). Early reports based on low-throughput small-RNA sequencing and computational
prediction technologies have not been recapitulated by other labs (60, 113). Thus, until it is
independently verified that HIV encodes bioactive miRNAs with relevant functionality, caution
is warranted toward any claims that HIV makes miRNAs. Additionally, HIV has been suggested
to use host miRNAs to regulate its transcripts (117, 118). However, Whisnant et al. (113) recently
demonstrated by using CLIP technologies that the HIV genome is largely resistant to host miRNA
regulation. This study verified that a small subset of the published miRNAs do in fact directly
contact a small fraction of HIV transcripts, but questions were raised as to whether this contact
is sufficient for meaningful bioactivity (113). It is worth noting that a lncRNA, NEAT1, has also
been shown to regulate HIV gene expression (119). Further studies are warranted to determine
the effects of host ncRNAs on the HIV life cycle.
A SUGGESTED ROLE FOR HOST MicroRNAs AS A
DIRECT ANTIVIRAL DEFENSE
In principle, host miRNA–mediated negative regulation of viruses falls into one of three categories:
(a) a natural host defense against specific viral pathogens, (b) a gene regulation tool employed by
the virus, or (c) a consequence of the laboratory system used that does not occur during natural
infection (120). Several papers have published models whereby miRNAs act as a direct defense
against specific pathogens (121–123). However, we note that others have questioned this interpretation because in some instances these host miRNAs are not expressed in a physiologically relevant
context (120, 124, 125). This criticism is supported by experimental evidence demonstrating that
some miRNAs are not at a sufficient copy number for bioactivity, or are not expressed in the appropriate host or cell type during natural infection (120, 124, 125). Any model whereby host miRNAs
serve to directly combat a specific virus will have to account for the inability of these viruses to
evolve resistance. This is especially problematic given that only a single nucleotide change can be
sufficient to abolish miRNA-mediated suppression (126). As discussed above, miRNA-mediated
negative regulation can be advantageous to the virus because diverse viruses encode their own
autoregulatory miRNAs. Indeed, some miRNA-mutant viruses replicate better in cell culture
and/or in vivo models (25, 27, 50, 90, 91). Yet, these viral miRNAs are maintained in the wild, and
their functionalities are typically conserved among divergent viruses (10, 53, 70, 75, 127). This
underscores the reality that standard laboratory assays sometimes do not recapitulate the proviral
advantages conveyed by miRNAs during natural infection.
As new data emerge, it may be worth revisiting some of the early reports claiming direct miRNA
antiviral effectors. In a notable study, Lecellier et al. (128) proposed that host miRNAs can be a
direct antiviral defense. They demonstrated that miR-32 can repress primate foamy virus 1 (PFV-1;
www.annualreviews.org • Viral MicroRNAs
99
VI01CH06-Sullivan
ARI
2 September 2014
Aptamer: typically an
oligonucleotide (can
be a protein) that
binds to a specific
target molecule
6:40
note that PFV-1 now refers to prototype foamy virus 1) accumulation through a docking site
located within the coding region of ORF2 that is also the 3 UTR of all the remaining PFV-1
mRNAs (128). Although this was argued as a miRNA-based antiviral defense, it remains to be
determined whether this interaction occurs to a meaningful degree in vivo and, if so, whether it is
disadvantageous to the fitness of the virus. Importantly, the recent discovery that PFV and other
SFVs encode highly expressed, evolutionarily conserved miRNAs (R.P. Kincaid, Y. Chen, J.E.
Cox, A. Rethwilm & C.S. Sullivan, unpublished observations) demonstrates that some miRNA
regulation is clearly advantageous to overall PFV fitness.
OTHER CLASSES OF VIRAL NONCODING RNAs
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
Decades before the discovery of miRNAs, virus-encoded ncRNAs were expected to play an important role in the infectious cycle (14). Several different viruses, including herpesviruses and
adenoviruses, encode robust amounts of longer ncRNAs (∼160 to >1,000 nt). Unlike miRNAs,
these ncRNAs likely represent a hodgepodge of different mechanisms of action, and as such, a
full understanding of how they function is still lacking. Two of these ncRNAs for which recent
insights have been reported include the adenovirus virus-associated (VA) RNAs and the KSHV
polyadenylated nuclear RNA.
VA RNAs are encoded by the lung- and gastrointestinal tract–tropic adenoviruses. These are
among the best studied and oldest known viral ncRNAs. These ∼165-nt RNAs are transcribed
by RNA polymerase III during the lytic cycle to 107 –108 copies/cell, ranking among the most
numerically abundant RNAs (14, 129). Both primate and human adenoviruses can express up to
two VA RNAs (130). VA I RNA functions like a natural aptamer that stoichiometrically binds
to and inhibits protein kinase R (PKR) (131). Thus, this represents an important counterdefense
used by the virus to evade the antiviral response. Additionally, VA I inhibition of PKR indirectly
promotes viral gene expression by limiting translational repression associated with PKR activation.
Interestingly, less than 1% of the VA RNAs is processed into miRNAs. Despite the inefficient
processing, VA-derived miRNAs are the most abundant miRNAs (∼106 copies/cell) detected in
a cell undergoing lytic infection (129). However, these miRNAs are likely not important during
lytic infection. Unlike VA-null viruses, which are attenuated for virus production by 1–2 orders of
magnitude, engineered mutant viruses that retain the larger VA structure but produce miRNAs
with altered seeds behave like wild-type viruses (129). Although much less studied, adenoviruses
can also produce a persistent infection (132, 133). Recently, it was shown in a cell culture model
of persistence that the VA-derived miRNAs are readily detectable and account for ∼2.7% of the
total RISC-associated RNAs (132, 134). Thus, it remains formally possible that VA miRNAs are
important during persistent infection or in other unknown contexts, but this possibility has not
yet been demonstrated (Figure 2).
KSHV encodes a 1.1-kb ncRNA called the polyadenylated nuclear RNA (PAN). PAN is expressed during lytic infection and is the most abundant viral transcript produced, topping out at
106 –107 copies/cell (135). Although polyadenylated, PAN is nuclear and has an atypical 3 end
structure that renders it resistant to nucleolytic turnover (136, 137). Until recently, no functions
for PAN had been reported. However, in the past few years, several exciting reports have been
published. Knockdown and knockout studies show that PAN is important for virus gene expression
(138, 139). Importantly, PAN is required for expression of RTA, the master lytic switch protein
(140). The published mechanism that can account for this is that PAN is a lncRNA that alters viral
chromatin (139). Very recently, a small fraction of PAN has been shown to be associated with
translationally active ribosomes (141). Though only a small fraction, this still would potentially
account for some of the most abundant virally derived peptides made during infection (141). The
100
Cox
·
Sullivan
VI01CH06-Sullivan
a
ARI
2 September 2014
6:40
b
Lytic infection
Persistent infection
Dampens
antiviral response
Protein
kinase R
RISC
?
Indirectly promotes
viral gene expression
Viral targets
Host targets
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
Figure 2
Model: role of virus-associated (VA) I RNA in adenovirus infection. (a) VA I RNAs are structured, highly abundant RNAs encoded by
some primate viruses (including human adenoviruses). During lytic infection, VA I RNAs stoichiometrically bind to protein kinase R
(PKR), preventing its activation. This limits the cellular antiviral response and prevents translation inhibition, thus allowing viral gene
expression (128). (b) VA I RNA, and the related VA II RNA in some adenoviruses, can be inefficiently processed into miRNAs. These
miRNAs are made during lytic infection but have also been detected in cell models of persistent infection (130). It is therefore possible
that the VA RNA–derived miRNAs function to maintain persistent infection, but such a model remains untested. Abbreviation:
RISC, RNA-induced silencing complex.
function(s) of these putative peptides and how translating polyribosomes are associated with the
(mostly?) nuclear-restricted PAN remain a mystery.
WHAT ARE THEY GOOD FOR?
With our current understanding of the impact of miRNAs on viral gene expression, miRNAs
represent a plausible avenue of antiviral therapeutics. Notably, human clinical trials are already
underway for therapeutics that target miR-122 to limit hepatitis C infection. Hepatitis C uses
miR-122 to positively regulate virus copy number (142, 143). The success of this work suggests
that targeting virally encoded miRNAs could also be a viable treatment strategy when the delivery
barrier of miRNA therapeutics can be overcome. Others have engineered multiple host miRNA
docking sites to restrict infection by gene therapy vectors (144–146). This approach shows promise
in limiting oncolytic viruses to tumor tissues. A similar approach has been developed to restrict
species specificity to laboratory model animals of highly pathogenic avian influenza (147). Finally,
in cases where viral genome copy number is limiting but miRNA copy number is high, viral
miRNAs may be useful as biomarkers of disease. For example, this method has been proposed for
early detection of a herpesvirus associated with a fatal disease in elephants (148, 149).
SUMMARY POINTS
1. Diverse viruses, including DNA viruses and retroviruses, encode miRNAs.
2. Many viral miRNAs target host and/or viral transcripts as a mechanism to regulate virus
gene expression.
3. miRNA regulation plays an important role in regulating persistent infection.
4. Host miRNAs are unlikely to be a direct defense against specific viral transcripts.
5. Viruses may use miRNAs as barometers to measure stress levels in host cells.
www.annualreviews.org • Viral MicroRNAs
101
VI01CH06-Sullivan
ARI
2 September 2014
6:40
6. Longer ncRNAs are emerging as important players in virus infection.
7. Manipulating miRNA regulation shows promise in optimizing viral gene therapy vectors.
FUTURE ISSUES
1. New studies of animal models are needed to establish the role of ncRNAs in viral persistence in vivo.
2. Determining the full repertoire of virus families that encode miRNAs will help us understand known viral miRNA functions.
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
3. Uncovering alternative mechanisms of regulation for persistent viruses that do not encode
miRNAs is clinically important.
4. Entire new classes of viral and host ncRNAs relevant to infection likely await discovery.
5. Viral ncRNAs offer new therapeutics and biomarkers strategies.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
This work was supported by National Institutes of Health grant R01AI077746, a Burroughs
Wellcome Investigators in Pathogenesis Award, Cancer Prevention and Research Institute of
Texas grant RP110098, a National Science Foundation CAREER award, and a University of
Texas at Austin Institute for Cellular and Molecular Biology fellowship.
LITERATURE CITED
1. Lee RC, Feinbaum RL, Ambros V. 1993. The C. elegans heterochronic gene lin-4 encodes small RNAs
with antisense complementarity to lin-14. Cell 75:843–54
2. Ulitsky I, Bartel DP. 2013. lincRNAs: genomics, evolution, and mechanisms. Cell 154:26–46
3. Wang KC, Chang HY. 2011. Molecular mechanisms of long noncoding RNAs. Mol. Cell 43:904–14
4. Baltimore D. 1971. Expression of animal virus genomes. Bacteriol. Rev. 35:235–41
5. Funk A, Truong K, Nagasaki T, Torres S, Floden N, et al. 2010. RNA structures required for production
of subgenomic flavivirus RNA. J. Virol. 84:11407–17
6. Grundhoff A, Sullivan CS. 2011. Virus-encoded microRNAs. Virology 411:325–43
7. Kincaid RP, Burke JM, Cox JC, de Villiers EM, Sullivan CS. 2013. A human torque teno virus encodes
a microRNA that inhibits interferon signaling. PLoS Pathog. 9:e1003818
8. Kincaid RP, Burke JM, Sullivan CS. 2012. RNA virus microRNA that mimics a B-cell oncomiR. Proc.
Natl. Acad. Sci. USA 109:3077–82
9. Yao Y, Smith LP, Nair V, Watson M. 2014. An avian retrovirus uses canonical expression and processing
mechanisms to generate viral microRNA. J. Virol. 88:2–9
10. Kincaid RP, Sullivan CS. 2012. Virus-encoded microRNAs: an overview and a look to the future. PLoS
Pathog. 8:e1003018
102
Cox
·
Sullivan
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
VI01CH06-Sullivan
ARI
2 September 2014
6:40
11. Sullivan CS. 2008. New roles for large and small viral RNAs in evading host defences. Nat. Rev. Genet.
9:503–7
12. Umbach JL, Cullen BR. 2009. The role of RNAi and microRNAs in animal virus replication and antiviral
immunity. Genes Dev. 23:1151–64
13. Boss IW, Renne R. 2010. Viral miRNAs: tools for immune evasion. Curr. Opin. Microbiol. 13:540–45
14. Sullivan CS, Cullen BR. 2009. Non-coding regulatory RNAs of the DNA tumor viruses. In DNA Tumor
Viruses, ed. B Damania, JM Pipas, pp. 645–82. New York: Springer
15. Sedger LM. 2013. MicroRNA control of interferons and interferon induced anti-viral activity. Mol.
Immunol. 56:781–93
16. Subramanian S, Steer CJ. 2010. MicroRNAs as gatekeepers of apoptosis. J. Cell. Physiol. 223:289–98
17. Chen CZ, Schaffert S, Fragoso R, Loh C. 2013. Regulation of immune responses and tolerance: the
microRNA perspective. Immunol. Rev. 253:112–28
18. Farazi TA, Hoell JI, Morozov P, Tuschl T. 2013. MicroRNAs in human cancer. Adv. Exp. Med. Biol.
774:1–20
19. Cullen BR. 2004. Transcription and processing of human microRNA precursors. Mol. Cell 16:861–65
20. Flynt AS, Lai EC. 2008. Biological principles of microRNA-mediated regulation: shared themes amid
diversity. Nat. Rev. Genet. 9:831–42
21. Zisoulis DG, Lovci MT, Wilbert ML, Hutt KR, Liang TY, et al. 2010. Comprehensive discovery of
endogenous Argonaute binding sites in Caenorhabditis elegans. Nat. Struct. Mol. Biol. 17:173–79
22. Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, et al. 2005. Microarray analysis shows
that some microRNAs downregulate large numbers of target mRNAs. Nature 433:769–73
23. Seo GJ, Chen CJ, Sullivan CS. 2009. Merkel cell polyomavirus encodes a microRNA with the ability to
autoregulate viral gene expression. Virology 383:183–87
24. Seo GJ, Fink LHL, O’Hara B, Atwood WJ, Sullivan CS. 2008. Evolutionarily conserved function of a
viral microRNA. J. Virol. 82:9823–28
25. Sullivan CS, Grundhoff AT, Tevethia S, Pipas JM, Ganem D. 2005. SV40-encoded microRNAs
regulate viral gene expression and reduce susceptibility to cytotoxic T cells. Nature 435:682–86
26. Barth S, Pfuhl T, Mamiani A, Ehses C, Roemer K, et al. 2008. Epstein–Barr virus–encoded microRNA
miR-BART2 down-regulates the viral DNA polymerase BALF5. Nucleic Acids Res. 36:666–75
27. Sullivan CS, Sung CK, Pack CD, Grundhoff A, Lukacher AE, et al. 2009. Murine polyomavirus encodes
a microRNA that cleaves early RNA transcripts but is not essential for experimental infection. Virology
387:157–67
28. Bhattacharyya SN, Habermacher R, Martine U, Closs EI, Filipowicz W. 2006. Stress-induced reversal
of microRNA repression and mRNA P-body localization in human cells. Cold Spring Harb. Symp. Quant.
Biol. 71:513–21
29. Leung AKL, Vyas S, Rood JE, Bhutkar A, Sharp PA, Chang P. 2011. Poly(ADP-ribose) regulates stress
responses and microRNA activity in the cytoplasm. Mol. Cell 42:489–99
30. Seo GJ, Kincaid RP, Phanaksri T, Burke JM, Pare JM, et al. 2013. Reciprocal inhibition between
intracellular antiviral signaling and the RNAi machinery in mammalian cells. Cell Host Microbe 14:435–
45
31. Bhattacharyya SN, Habermacher R, Martine U, Closs EI, Filipowicz W. 2006. Relief of microRNAmediated translational repression in human cells subjected to stress. Cell 125:1111–24
32. Vasudevan S, Tong Y, Steitz JA. 2007. Switching from repression to activation: microRNAs can upregulate translation. Science 318:1931–34
33. Vasudevan S, Steitz JA. 2007. AU-rich-element-mediated upregulation of translation by FXR1 and
Argonaute 2. Cell 128:1105–18
34. Ebert MS, Sharp PA. 2012. Roles for microRNAs in conferring robustness to biological processes. Cell
149:515–24
35. Cassidy JJ, Jha AR, Posadas DM, Giri R, Venken KJT, et al. 2013. miR-9a minimizes the phenotypic
impact of genomic diversity by buffering a transcription factor. Cell 155:1556–67
36. Mendell JT, Olson EN. 2012. MicroRNAs in stress signaling and human disease. Cell 148:1172–87
37. Peláez N, Carthew RW. 2012. Biological robustness and the role of microRNAs: a network perspective.
Curr. Top. Dev. Biol. 99:237–55
www.annualreviews.org • Viral MicroRNAs
25. First demonstration
of a viral miRNA
target—the
autoregulation of T
antigen transcripts.
103
VI01CH06-Sullivan
ARI
2 September 2014
39. Demonstrated that
viral miRNAs can
regulate several
different viral
transcripts.
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
40. First to suggest that
miRNAs may regulate
numerous viral
transcripts in different
herpesviruses.
44. Demonstrated that
HSV-1 encodes
autoregulatory
miRNAs; implied a role
in maintaining latency.
50. An HSV-1 miRNA
deletion mutant shows
increased replication
under only some
experimental
conditions.
104
6:40
38. Kozomara A, Griffiths-Jones S. 2011. miRBase: integrating microRNA annotation and deep-sequencing
data. Nucleic Acids Res. 39:D152–57
39. Grey F, Meyers H, White EA, Spector DH, Nelson J. 2007. A human cytomegalovirus-encoded
microRNA regulates expression of multiple viral genes involved in replication. PLoS Pathog.
3:e163
40. Murphy E, Vanı́cek J, Robins H, Shenk T, Levine AJ. 2008. Suppression of immediate-early viral
gene expression by herpesvirus-coded microRNAs: implications for latency. Proc. Natl. Acad. Sci.
USA 105:5453–58
41. Forte E, Luftig MA. 2011. The role of microRNAs in Epstein–Barr virus latency and lytic reactivation.
Microbes Infect. 13:1156–67
42. Lieberman PM. 2013. Keeping it quiet: chromatin control of gammaherpesvirus latency. Nat. Rev.
Microbiol. 11:863–75
43. Wilson AC, Mohr I. 2012. A cultured affair: HSV latency and reactivation in neurons. Trends Microbiol.
20:604–11
44. Umbach JL, Kramer MF, Jurak I, Karnowski HW, Coen DM, Cullen BR. 2008. MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs. Nature 454:780–
83
45. Jurak I, Griffiths A, Coen DM. 2011. Mammalian alphaherpesvirus miRNAs. Biochim. Biophys. Acta
1809:641–53
46. Boutell C, Everett RD. 2013. Regulation of alphaherpesvirus infections by the ICP0 family of proteins.
J. Gen. Virol. 94:465–81
47. Everett RD. 2000. ICP0, a regulator of herpes simplex virus during lytic and latent infection. BioEssays
22:761–70
48. Everett RD, Parsy ML, Orr A. 2009. Analysis of the functions of herpes simplex virus type 1 regulatory
protein ICP0 that are critical for lytic infection and derepression of quiescent viral genomes. J. Virol.
83:4963–77
49. Smith MC, Boutell C, Davido DJ. 2011. HSV-1 ICP0: paving the way for viral replication. Future Virol.
6:421–29
50. Flores O, Nakayama S, Whisnant AW, Javanbakht H, Cullen BR, Bloom DC. 2013. Mutational
inactivation of herpes simplex virus 1 microRNAs identifies viral mRNA targets and reveals
phenotypic effects in culture. J. Virol. 87:6589–603
51. Dölken L, Pfeffer S, Koszinowski UH. 2009. Cytomegalovirus microRNAs. Virus Genes 38:355–64
52. Huang Y, Qi Y, Ma Y, He R, Ji Y, et al. 2013. Down-regulation of human cytomegalovirus UL138, a
novel latency-associated determinant, by hcmv-miR-UL36. J. Biosci. 38:479–85
53. Hancock MH, Tirabassi RS, Nelson JA. 2012. Rhesus cytomegalovirus encodes seventeen microRNAs
that are differentially expressed in vitro and in vivo. Virology 425:133–42
54. Stern-Ginossar N, Saleh N, Goldberg MD, Prichard M, Wolf DG, Mandelboim O. 2009. Analysis of
human cytomegalovirus–encoded microRNA activity during infection. J. Virol. 83:10684–93
55. Fu M, Gao Y, Zhou Q, Zhang Q, Peng Y, et al. 2014. Human cytomegalovirus latent infection alters
the expression of cellular and viral microRNA. Gene 536:272–78
56. Dölken L, Krmpotic A, Kothe S, Tuddenham L, Tanguy M, et al. 2010. Cytomegalovirus microRNAs
facilitate persistent virus infection in salivary glands. PLoS Pathog. 6:e1001150
57. Gottwein E, Corcoran DL, Mukherjee N, Skalsky RL, Hafner M, et al. 2011. Viral microRNA targetome
of KSHV-infected primary effusion lymphoma cell lines. Cell Host Microbe 10:515–26
58. Grundhoff A, Sullivan CS, Ganem D. 2006. A combined computational and microarray-based approach
identifies novel microRNAs encoded by human gamma-herpesviruses. RNA 12:733–50
59. Haecker I, Gay LA, Yang Y, Hu J, Morse AM, et al. 2012. Ago HITS-CLIP expands understanding of
Kaposi’s sarcoma–associated herpesvirus miRNA function in primary effusion lymphomas. PLoS Pathog.
8:e1002884
60. Pfeffer S, Sewer A, Lagos-Quintana M, Sheridan R, Sander C, et al. 2005. Identification of microRNAs
of the herpesvirus family. Nat. Methods 2:269–76
61. Zhu Y, Haecker I, Yang Y, Gao SJ, Renne R. 2013. γ-Herpesvirus-encoded miRNAs and their roles in
viral biology and pathogenesis. Curr. Opin. Virol. 3:266–75
Cox
·
Sullivan
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
VI01CH06-Sullivan
ARI
2 September 2014
6:40
62. Lukac DM, Kirshner JR, Ganem D. 1999. Transcriptional activation by the product of open reading
frame 50 of Kaposi’s sarcoma–associated herpesvirus is required for lytic viral reactivation in B cells.
J. Virol. 73:9348–61
63. Lin X, Liang D, He Z, Deng Q, Robertson ES, Lan K. 2011. miR-K12-7-5p encoded by Kaposi’s
sarcoma–associated herpesvirus stabilizes the latent state by targeting viral ORF50/RTA. PLoS ONE
6:e16224
64. Lu F, Stedman W, Yousef M, Renne R, Lieberman PM. 2010. Epigenetic regulation of Kaposi’s
sarcoma–associated herpesvirus latency by virus-encoded microRNAs that target Rta and the
cellular Rbl2-DNMT pathway. J. Virol. 84:2697–706
65. Lei X, Bai Z, Ye F, Xie J, Kim CG, et al. 2010. Regulation of NF-κB inhibitor IκBα and viral
replication by a KSHV microRNA. Nat. Cell Biol. 12:193–99
66. Liang D, Gao Y, Lin X, He Z, Zhao Q, et al. 2011. A human herpesvirus miRNA attenuates interferon
signaling and contributes to maintenance of viral latency by targeting IKKε. Cell Res. 21:793–806
67. Lu CC, Li Z, Chu CY, Feng J, Feng J, et al. 2010. MicroRNAs encoded by Kaposi’s sarcoma–associated
herpesvirus regulate viral life cycle. EMBO Rep. 11:784–90
68. Moody R, Zhu Y, Huang Y, Cui X, Jones T, et al. 2013. KSHV microRNAs mediate cellular transformation and tumorigenesis by redundantly targeting cell growth and survival pathways. PLoS Pathog.
9:e1003857
69. Ziegelbauer JM, Sullivan CS, Ganem D. 2009. Tandem array–based expression screens identify host
mRNA targets of virus-encoded microRNAs. Nat. Genet. 41:130–34
70. Umbach JL, Strelow LI, Wong SW, Cullen BR. 2010. Analysis of rhesus rhadinovirus microRNAs
expressed in virus-induced tumors from infected rhesus macaques. Virology 405:592–99
71. Bruce AG, Ryan JT, Thomas MJ, Peng X, Grundhoff A, et al. 2013. Next-generation sequence analysis
of the genome of RFHVMn, the macaque homolog of Kaposi’s sarcoma (KS)-associated herpesvirus,
from a KS-like tumor of a pig-tailed macaque. J. Virol. 87:13676–93
72. Bai Z, Huang Y, Li W, Zhu Y, Jung JU, et al. 2014. Genomewide mapping and screening of Kaposi’s
sarcoma–associated herpesvirus (KSHV) 3 untranslated regions identify bicistronic and polycistronic
viral transcripts as frequent targets of KSHV microRNAs. J. Virol. 88:377–92
73. McClure LV, Kincaid RP, Burke JM, Grundhoff A, Sullivan CS. 2013. Comprehensive mapping and
analysis of Kaposi’s sarcoma–associated herpesvirus 3 UTRs identify differential posttranscriptional
control of gene expression in lytic versus latent infection. J. Virol. 87:12838–49
74. Lin YT, Sullivan CS. 2011. Expanding the role of Drosha to the regulation of viral gene expression.
Proc. Natl. Acad. Sci. USA 108:11229–34
75. Cai X, Schäfer A, Lu S, Bilello JP, Desrosiers RC, et al. 2006. Epstein–Barr virus microRNAs are
evolutionarily conserved and differentially expressed. PLoS Pathog. 2:e23
76. Pfeffer S, Zavolan M, Grässer FA, Chien M, Russo JJ, et al. 2004. Identification of virus-encoded
microRNAs. Science 304:734–36
77. Riley KJ, Rabinowitz GS, Yario TA, Luna JM, Darnell RB, Steitz JA. 2012. EBV and human microRNAs
co-target oncogenic and apoptotic viral and human genes during latency. EMBO J. 31:2207–21
78. Iizasa H, Wulff BE, Alla NR, Maragkakis M, Megraw M, et al. 2010. Editing of Epstein–Barr virus–
encoded BART6 microRNAs controls their Dicer targeting and consequently affects viral latency.
J. Biol. Chem. 285:33358–70
79. Seto E, Moosmann A, Grömminger S, Walz N, Grundhoff A, Hammerschmidt W. 2010. Micro RNAs
of Epstein–Barr virus promote cell cycle progression and prevent apoptosis of primary human B cells.
PLoS Pathog. 6:e1001063
80. DeCaprio JA, Garcea RL. 2013. A cornucopia of human polyomaviruses. Nat. Rev. Microbiol. 11:264–76
81. Korup S, Rietscher J, Calvignac-Spencer S, Trusch F, Hofmann J, et al. 2013. Identification of a novel
human polyomavirus in organs of the gastrointestinal tract. PLoS ONE 8:e58021
82. Delbue S, Ferraresso M, Ghio L, Carloni C, Carluccio S, et al. 2013. A review on JC virus infection in
kidney transplant recipients. Clin. Dev. Immunol. 2013:926391
83. Hirsch HH, Kardas P, Kranz D, Leboeuf C. 2013. The human JC polyomavirus ( JCPyV): virological
background and clinical implications. APMIS 121:685–727
www.annualreviews.org • Viral MicroRNAs
64. Demonstrated that
deletion of 10 of 12
KSHV pre-miRNAs
results in increased lytic
infection.
65. Demonstrated that a
KSHV miRNA can
control viral replication
through the NFκB
pathway.
76. First publication of
viral miRNAs;
suggested that
miR-BART2 directly
regulates the BALF5
polymerase transcript.
105
ARI
2 September 2014
6:40
84. Rinaldo CH, Tylden GD, Sharma BN. 2013. The human polyomavirus BK (BKPyV): virological background and clinical implications. APMIS 121:728–45
85. Kazem S, van der Meijden E, Feltkamp MCW. 2013. The trichodysplasia spinulosa–associated polyomavirus: virological background and clinical implications. APMIS 121:770–82
86. Cole CN. 1996. Polyomaviridae: the viruses and their replication. In Fields Virology, ed. DM Knipe, PM
Howley, pp. 1997–2043. Philadelphia: Lippincott-Raven. 3rd ed.
87. Cantalupo P, Doering A, Sullivan CS, Pal A, Peden KWC, et al. 2005. Complete nucleotide sequence
of polyomavirus SA12. J. Virol. 79:13094–104
88. Chen CJ, Cox JE, Kincaid RP, Martinez A, Sullivan CS. 2013. Divergent microRNA targetomes of
closely related circulating strains of a polyomavirus. J. Virol. 87:11135–47
89. Chen CJ, Kincaid RP, Seo GJ, Bennett MD, Sullivan CS. 2011. Insights into Polyomaviridae microRNA
function derived from study of the bandicoot papillomatosis carcinomatosis viruses. J. Virol. 85:4487–500
90. Broekema NM, Imperiale MJ. 2013. miRNA regulation of BK polyomavirus replication during early
infection. Proc. Natl. Acad. Sci. USA 110:8200–5
91. Zhang S, Sroller V, Zanwar P, Chen CJ, Halvorson SJ, et al. 2014. Viral microRNA effects on pathogenesis of polyomavirus SV40 infections in Syrian golden hamsters. PLoS Pathogens 10:e1003912
92. Goff SP. 2001. Retroviridae: the retroviruses and their replication. In Fields Virology, ed. DM Knipe,
PM Howley, DE Griffin, RA Lamb, MA Martin, B Roizman, pp. 1871–922. Philadelphia: Lippincott
Williams & Wilkins. 4th ed.
93. Lin J, Cullen BR. 2007. Analysis of the interaction of primate retroviruses with the human RNA interference machinery. J. Virol. 81:12218–26
94. Schmidt M, Herchenröder O, Heeney J, Rethwilm A. 1997. Long terminal repeat U3 length polymorphism of human foamy virus. Virology 230:167–78
95. Rethwilm A, Baunach G, Netzer KO, Maurer B, Borisch B, ter Meulen V. 1990. Infectious DNA of the
human spumaretrovirus. Nucleic Acids Res. 18:733–38
96. Neves M, Périès J, Saı̈b A. 1998. Study of human foamy virus proviral integration in chronically infected
murine cells. Res. Virol. 149:393–401
97. Gregory SM, West JA, Dillon PJ, Hilscher C, Dittmer DP, Damania B. 2009. Toll-like receptor signaling
controls reactivation of KSHV from latency. Proc. Natl. Acad. Sci. USA 106:11725–30
98. Li X, Feng J, Sun R. 2011. Oxidative stress induces reactivation of Kaposi’s sarcoma–associated herpesvirus and death of primary effusion lymphoma cells. J. Virol. 85:715–24
99. Lu C, Zeng Y, Huang Z, Huang L, Qian C, et al. 2005. Human herpesvirus 6 activates lytic cycle
replication of Kaposi’s sarcoma–associated herpesvirus. Am. J. Pathol. 166:173–83
100. Palmisano I, Della Chiara G, D’Ambrosio RL, Huichalaf C, Brambilla P, et al. 2012. Amino acid starvation induces reactivation of silenced transgenes and latent HIV-1 provirus via down-regulation of histone
deacetylase 4 (HDAC4). Proc. Natl. Acad. Sci. USA 109:E2284–93
101. Qin D, Zeng Y, Qian C, Huang Z, Lv Z, et al. 2008. Induction of lytic cycle replication of Kaposi’s
sarcoma–associated herpesvirus by herpes simplex virus type 1: involvement of IL-10 and IL-4. Cell
Microbiol. 10:713–28
102. Taylor GM, Raghuwanshi SK, Rowe DT, Wadowsky RM, Rosendorff A. 2011. Endoplasmic reticulum
stress causes EBV lytic replication. Blood 118:5528–39
103. Vieira J, O’Hearn P, Kimball L, Chandran B, Corey L. 2001. Activation of Kaposi’s sarcoma–associated
herpesvirus (human herpesvirus 8) lytic replication by human cytomegalovirus. J. Virol. 75:1378–86
104. Cai X, Li G, Laimins LA, Cullen BR. 2006. Human papillomavirus genotype 31 does not express
detectable microRNA levels during latent or productive virus replication. J. Virol. 80:10890–93
105. Gunasekharan V, Laimins LA. 2013. Human papillomaviruses modulate microRNA 145 expression to
directly control genome amplification. J. Virol. 87:6037–43
106. Crow JM. 2012. HPV: the global burden. Nature 488:S2–3
107. Gu W, An J, Ye P, Zhao KN, Antonsson A. 2011. Prediction of conserved microRNAs from skin and
mucosal human papillomaviruses. Arch. Virol. 156:1161–71
108. Qian K, Pietilä T, Rönty M, Michon F, Frilander MJ, et al. 2013. Identification and validation of human
papillomavirus encoded microRNAs. PLoS ONE 8:e70202
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
VI01CH06-Sullivan
106
Cox
·
Sullivan
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
VI01CH06-Sullivan
ARI
2 September 2014
6:40
109. Doorbar J. 2005. The papillomavirus life cycle. J. Clin. Virol. 32(Suppl. 1):S7–15
110. Zacks MA, Paessler S. 2010. Encephalitic alphaviruses. Vet. Microbiol. 140:281–86
111. Weaver SC. 2005. Host range, amplification and arboviral disease emergence. In Infectious Diseases from
Nature: Mechanisms of Viral Emergence and Persistence, ed. CJ Peters, CH Calisher, pp. 33–44. Vienna:
Springer
112. Trobaugh DW, Gardner CL, Sun C, Haddow AD, Wang E, et al. 2013. RNA viruses can hijack
vertebrate microRNAs to suppress innate immunity. Nature 506:245–48
113. Whisnant AW, Bogerd HP, Flores O, Ho P, Powers JG, et al. 2013. In-depth analysis of the interaction
of HIV-1 with cellular microRNA biogenesis and effector mechanisms. mBio 4:e000193
114. Klase Z, Kale P, Winograd R, Gupta MV, Heydarian M, et al. 2007. HIV-1 TAR element is processed
by Dicer to yield a viral micro-RNA involved in chromatin remodeling of the viral LTR. BMC Mol. Biol.
8:63
115. Omoto S, Ito M, Tsutsumi Y, Ichikawa Y, Okuyama H, et al. 2004. HIV-1 nef suppression by virally
encoded microRNA. Retrovirology 1:44
116. Schopman NCT, Willemsen M, Liu YP, Bradley T, van Kampen A, et al. 2012. Deep sequencing of
virus-infected cells reveals HIV-encoded small RNAs. Nucleic Acids Res. 40:414–27
117. Ahluwalia JK, Khan SZ, Soni K, Rawat P, Gupta A, et al. 2008. Human cellular microRNA hsa-miR-29a
interferes with viral nef protein expression and HIV-1 replication. Retrovirology 5:117
118. Huang J, Wang F, Argyris E, Chen K, Liang Z, et al. 2007. Cellular microRNAs contribute to HIV-1
latency in resting primary CD4+ T lymphocytes. Nat. Med. 13:1241–47
119. Zhang Q, Chen CY, Yedavalli VSRK, Jeang KT. 2013. NEAT1 long noncoding RNA and paraspeckle
bodies modulate HIV-1 posttranscriptional expression. mBio 4:e00596–12
120. Skalsky RL, Cullen BR. 2010. Viruses, microRNAs, and host interactions. Annu. Rev. Microbiol. 64:123–
41
121. Huang T, Zhang X. 2012. Functional analysis of a crustacean microRNA in host-virus interactions.
J. Virol. 86:12997–3004
122. Kelly EJ, Nace R, Barber GN, Russell SJ. 2010. Attenuation of vesicular stomatitis virus encephalitis
through microRNA targeting. J. Virol. 84:1550–62
123. Pedersen IM, Cheng G, Wieland S, Volinia S, Croce CM, et al. 2007. Interferon modulation of cellular
microRNAs as an antiviral mechanism. Nature 449:919–22
124. Cullen BR. 2013. How do viruses avoid inhibition by endogenous cellular microRNAs? PLoS Pathog.
9:e1003694
125. Sarasin-Filipowicz M, Krol J, Markiewicz I, Heim MH, Filipowicz W. 2009. Decreased levels of microRNA miR-122 in individuals with hepatitis C responding poorly to interferon therapy. Nat. Med.
15:31–33
126. Berezikov E. 2011. Evolution of microRNA diversity and regulation in animals. Nat. Rev. Genet. 12:846–
60
127. Skalsky RL, Kang D, Linnstaedt SD, Cullen BR. 2014. Evolutionary conservation of primate lymphocryptovirus microRNA targets. J. Virol. 88:1617–35
128. Lecellier C-H, Dunoyer P, Arar K, Lehmann-Che J, Eyquem S, et al. 2005. A cellular microRNA
mediates antiviral defense in human cells. Science 308:557–60
129. Kamel W, Segerman B, Öberg D, Punga T, Akusjärvi G. 2013. The adenovirus VA RNA–derived
miRNAs are not essential for lytic virus growth in tissue culture cells. Nucleic Acids Res. 41:4802–12
130. Ma Y, Mathews MB. 1996. Structure, function, and evolution of adenovirus-associated RNA: a phylogenetic approach. J. Virol. 70:5083–99
131. Maran A, Mathews MB. 1988. Characterization of the double-stranded RNA implicated in the inhibition
of protein synthesis in cells infected with a mutant adenovirus defective for VA RNA. Virology 164:106–13
132. Furuse Y, Ornelles DA, Cullen BR. 2013. Persistently adenovirus-infected lymphoid cells express microRNAs derived from the viral VAI and especially VAII RNA. Virology 447:140–45
133. Garnett CT, Erdman D, Xu W, Gooding LR. 2002. Prevalence and quantitation of species C adenovirus
DNA in human mucosal lymphocytes. J. Virol. 76:10608–16
134. Aparicio O, Razquin N, Zaratiegui M, Narvaiza I, Fortes P. 2006. Adenovirus virus-associated RNA is
processed to functional interfering RNAs involved in virus production. J. Virol. 80:1376–84
www.annualreviews.org • Viral MicroRNAs
112. Demonstrated that
host miRNAs can
restrict tissue tropism
of virus infection in a
nonengineered setting.
107
ARI
2 September 2014
6:40
135. Sun R, Lin SF, Gradoville L, Miller G. 1996. Polyadenylylated nuclear RNA encoded by Kaposi sarcoma–
associated herpesvirus. Proc. Natl. Acad. Sci. USA 93:11883–88
136. Mitton-Fry RM, DeGregorio SJ, Wang J, Steitz TA, Steitz JA. 2010. Poly(A) tail recognition by a viral
RNA element through assembly of a triple helix. Science 330:1244–47
137. Conrad NK, Mili S, Marshall EL, Shu MD, Steitz JA. 2006. Identification of a rapid mammalian
deadenylation-dependent decay pathway and its inhibition by a viral RNA element. Mol. Cell 24:943–53
138. Borah S, Darricarrère N, Darnell A, Myoung J, Steitz JA. 2011. A viral nuclear noncoding RNA binds relocalized poly(A) binding protein and is required for late KSHV gene expression. PLoS Pathog. 7:e1002300
139. Rossetto CC, Tarrant-Elorza M, Verma S, Purushothaman P, Pari GS. 2013. Regulation of viral
and cellular gene expression by Kaposi’s sarcoma–associated herpesvirus polyadenylated nuclear RNA.
J. Virol. 87:5540–53
140. Rossetto CC, Pari G. 2012. KSHV PAN RNA associates with demethylases UTX and JMJD3 to activate
lytic replication through a physical interaction with the virus genome. PLoS Pathog. 8:e1002680
141. Arias C, Weisburd B, Stern-Ginossar N, Mercier A, Madrid AS, et al. 2014. KSHV 2.0: a comprehensive
annotation of the Kaposi’s sarcoma–associated herpesvirus genome using next-generation sequencing
reveals novel genomic and functional features. PLoS Pathog. 10:e1003847
142. Haussecker D, Kay MA. 2010. miR-122 continues to blaze the trail for microRNA therapeutics. Mol.
Ther. 18:240–42
143. Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P. 2005. Modulation of hepatitis C virus RNA
abundance by a liver-specific microRNA. Science 309:1577–81
144. tenOever B. 2009. MicroManipulating viral-based therapeutics. Discov. Med. 8:51–54
145. Ibrišimović M, Kneidinger D, Lion T, Klein R. 2013. An adenoviral vector–based expression and delivery
system for the inhibition of wild-type adenovirus replication by artificial microRNAs. Antiviral Res.
97:10–23
146. Ylösmäki E, Hakkarainen T, Hemminki A, Visakorpi T, Andino R, Saksela K. 2008. Generation of a
conditionally replicating adenovirus based on targeted destruction of E1A mRNA by a cell type–specific
microRNA. J. Virol. 82:11009–15
147. Langlois RA, Albrecht RA, Kimble B, Sutton T, Shapiro JS, et al. 2013. MicroRNA-based strategy to
mitigate the risk of gain-of-function influenza studies. Nat. Biotechnol. 31:844–47
148. Gall A, Palser A. 2013. An elephantine viral problem. Nat. Rev. Microbiol. 11:512
149. Furuse Y, Dastjerdi A, Steinbach F, Cullen BR. 2014. Analysis of viral microRNA expression by elephant
endotheliotropic herpesvirus 1. Virology 454–55:102–8
150. Ross N, Gandhi MK, Nourse JP. 2013. The Epstein–Barr virus microRNA BART11-5p targets the early
B-cell transcription factor EBF1. Am. J. Blood Res. 3:210–24
151. Lung RW, Tong JH, Sung Y, Leung P, Ng DC, et al. 2009. Modulation of LMP2A expression by a
newly identified Epstein–Barr virus–encoded microRNA miR-BART22. Neoplasia 11:1174–84
152. Tang S, Patel A, Krause PR. 2009. Novel less-abundant viral microRNAs encoded by herpes simplex
virus 2 latency-associated transcript and their roles in regulating ICP34.5 and ICP0 mRNAs. J. Virol.
83:1433–42
153. Tang S, Bertke AS, Patel A, Wang K, Cohen JI, Krause PR. 2008. An acutely and latently expressed
herpes simplex virus 2 viral microRNA inhibits expression of ICP34.5, a viral neurovirulence factor. Proc.
Natl. Acad. Sci. USA 105:10931–36
154. Jaber T, Workman A, Jones C. 2010. Small noncoding RNAs encoded within the bovine herpesvirus 1
latency-related gene can reduce steady-state levels of infected cell protein 0 (bICP0). J. Virol. 84:6297–
307
155. Waidner LA, Burnside J, Anderson AS, Bernberg EL, German MA, et al. 2011. A microRNA of infectious
laryngotracheitis virus can downregulate and direct cleavage of ICP4 mRNA. Virology 411:25–31
156. Muylkens B, Coupeau D, Dambrine G, Trapp S, Rasschaert D. 2010. Marek’s disease virus microRNA
designated Mdv1-pre-miR-M4 targets both cellular and viral genes. Arch. Virol. 155:1823–37
157. Strassheim S, Stik G, Rasschaert D, Laurent S. 2012. Mdv1-miR-M7-5p, located in the newly identified
first intron of the latency-associated transcript of Marek’s disease virus, targets the immediate-early genes
ICP4 and ICP27. J. Gen. Virol. 93:1731–42
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
VI01CH06-Sullivan
108
Cox
·
Sullivan
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
VI01CH06-Sullivan
ARI
2 September 2014
6:40
158. Singh CP, Singh J, Nagaraju J. 2012. A baculovirus-encoded microRNA (miRNA) suppresses its host
miRNA biogenesis by regulating the Exportin-5 cofactor Ran. J. Virol. 86:7867–79
159. Hussain M, Taft RJ, Asgari S. 2008. An insect virus–encoded microRNA regulates viral replication.
J. Virol. 82:9164–70
160. Wu YL, Wu CP, Liu CYY, Hsu PWC, Wu EC, Chao YC. 2011. A non-coding RNA of insect HzNV-1
virus establishes latent viral infection through microRNA. Sci. Rep. 1:60
161. He Y, Yang K, Zhang X. 2014. Viral microRNAs targeting virus genes promote virus infection in shrimp
in vivo. J. Virol. 88:1104–12
162. Yanagawa-Matsuda A, Kitamura T, Higashino F, Yamano S, Totsuka Y, Shindoh M. 2012. E1A expression might be controlled by miR-214 in cells with low adenovirus productivity. Virus Res. 170:85–90
163. Sagan SM, Sarnow P, Wilson JA. 2013. Modulation of GB virus B RNA abundance by microRNA-122:
dependence on and escape from microRNA-122 restriction. J. Virol. 87:7338–47
164. Zhang G, Li Y, Zheng S, Liu M, Li X, Tang H. 2010. Suppression of hepatitis B virus replication by
microRNA-199a-3p and microRNA-210. Antiviral Res. 88:169–75
165. Yan Q, Li W, Tang Q, Yao S, Lv Z, et al. 2013. Cellular microRNAs 498 and 320d regulate herpes
simplex virus 1 induction of Kaposi’s sarcoma–associated herpesvirus lytic replication by targeting RTA.
PLoS ONE 8:e55832
166. Ma YJ, Yang J, Fan XL, Zhao HB, Hu W, et al. 2012. Cellular microRNA let-7c inhibits M1 protein
expression of the H1N1 influenza A virus in infected human lung epithelial cells. J. Cell. Mol. Med.
16:2539–46
167. Sun JZ, Wang J, Yuan D, Wang S, Li Z, et al. 2013. Cellular microRNA miR-181b inhibits replication
of mink enteritis virus by repression of non-structural protein 1 translation. PLoS ONE 8:e81515
168. Wen B, Dai H, Yang Y, Zhuang Y, Sheng R. 2013. MicroRNA-23b inhibits enterovirus 71 replication
through downregulation of EV71 VPL protein. Intervirology 56:195–200
169. Zheng Z, Ke X, Wang M, He S, Li Q, et al. 2013. Human microRNA hsa-miR-296-5p suppresses
enterovirus 71 replication by targeting the viral genome. J. Virol. 87:5645–56
170. Wang L, Qin Y, Tong L, Wu S, Wang Q, et al. 2012. miR-342-5p suppresses coxsackievirus B3 biosynthesis by targeting the 2C-coding region. Antiviral Res. 93:270–79
171. Tong L, Lin L, Wu S, Guo Z, Wang T, et al. 2013. Mir-10a∗ up-regulates coxsackievirus B3 biosynthesis
by targeting the 3D-coding sequence. Nucleic Acids Res. 41:3760–71
172. Sisk JM, Witwer KW, Tarwater PM, Clements JE. 2013. SIV replication is directly downregulated by
four antiviral miRNAs. Retrovirology 10:95
www.annualreviews.org • Viral MicroRNAs
109
VI01-FrontMatter
ARI
19 August 2014
7:19
Contents
Annual Review of
Virology
Volume 1, 2014
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
Forty Years with Emerging Viruses
C.J. Peters p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Inventing Viruses
William C. Summers p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p25
PHIRE and TWiV : Experiences in Bringing Virology to New Audiences
Graham F. Hatfull and Vincent Racaniello p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p37
Viruses and the Microbiota
Christopher M. Robinson and Julie K. Pfeiffer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p55
Role of the Vector in Arbovirus Transmission
Michael J. Conway, Tonya M. Colpitts, and Erol Fikrig p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p71
Balance and Stealth: The Role of Noncoding RNAs in the Regulation of
Virus Gene Expression
Jennifer E. Cox and Christopher S. Sullivan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p89
Thinking Outside the Triangle: Replication Fidelity of the Largest RNA
Viruses
Everett Clinton Smith, Nicole R. Sexton, and Mark R. Denison p p p p p p p p p p p p p p p p p p p p p p p p p 111
The Placenta as a Barrier to Viral Infections
Elizabeth Delorme-Axford, Yoel Sadovsky, and Carolyn B. Coyne p p p p p p p p p p p p p p p p p p p p p p p 133
Cytoplasmic RNA Granules and Viral Infection
Wei-Chih Tsai and Richard E. Lloyd p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 147
Mechanisms of Virus Membrane Fusion Proteins
Margaret Kielian p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 171
Oncolytic Poxviruses
Winnie M. Chan and Grant McFadden p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 191
Herpesvirus Genome Integration into Telomeric Repeats of Host Cell
Chromosomes
Nikolaus Osterrieder, Nina Wallaschek, and Benedikt B. Kaufer p p p p p p p p p p p p p p p p p p p p p p p p 215
ix
VI01-FrontMatter
ARI
19 August 2014
7:19
Viral Manipulation of Plant Host Membranes
Jean-François Laliberté and Huanquan Zheng p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 237
IFITM-Family Proteins: The Cell’s First Line of Antiviral Defense
Charles C. Bailey, Guocai Zhong, I-Chueh Huang, and Michael Farzan p p p p p p p p p p p p p p p 261
Glycan Engagement by Viruses: Receptor Switches and Specificity
Luisa J. Ströh and Thilo Stehle p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 285
Remarkable Mechanisms in Microbes to Resist Phage Infections
Ron L. Dy, Corinna Richter, George P.C. Salmond, and Peter C. Fineran p p p p p p p p p p p p p 307
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
Polydnaviruses: Nature’s Genetic Engineers
Michael R. Strand and Gaelen R. Burke p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 333
Human Cytomegalovirus: Coordinating Cellular Stress, Signaling,
and Metabolic Pathways
Thomas Shenk and James C. Alwine p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 355
Vaccine Development as a Means to Control Dengue Virus Pathogenesis:
Do We Know Enough?
Theodore C. Pierson and Michael S. Diamond p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 375
Archaeal Viruses: Diversity, Replication, and Structure
Nikki Dellas, Jamie C. Snyder, Benjamin Bolduc, and Mark J. Young p p p p p p p p p p p p p p p p p 399
AAV-Mediated Gene Therapy for Research and Therapeutic Purposes
R. Jude Samulski and Nicholas Muzyczka p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 427
Three-Dimensional Imaging of Viral Infections
Cristina Risco, Isabel Fernández de Castro, Laura Sanz-Sánchez, Kedar Narayan,
Giovanna Grandinetti, and Sriram Subramaniam p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 453
New Methods in Tissue Engineering: Improved Models for Viral
Infection
Vyas Ramanan, Margaret A. Scull, Timothy P. Sheahan, Charles M. Rice,
and Sangeeta N. Bhatia p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 475
Live Cell Imaging of Retroviral Entry
Amy E. Hulme and Thomas J. Hope p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 501
Parvoviruses: Small Does Not Mean Simple
Susan F. Cotmore and Peter Tattersall p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 517
Naked Viruses That Aren’t Always Naked: Quasi-Enveloped Agents of
Acute Hepatitis
Zongdi Feng, Asuka Hirai-Yuki, Kevin L. McKnight, and Stanley M. Lemon p p p p p p p p p 539
x
Contents
VI01-FrontMatter
ARI
19 August 2014
7:19
In Vitro Assembly of Retroviruses
Di L. Bush and Volker M. Vogt p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 561
The Impact of Mass Spectrometry–Based Proteomics on Fundamental
Discoveries in Virology
Todd M. Greco, Benjamin A. Diner, and Ileana M. Cristea p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 581
Viruses and the DNA Damage Response: Activation and Antagonism
Micah A. Luftig p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 605
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
Errata
An online log of corrections to Annual Review of Virology articles may be found at
http://www.annualreviews.org/errata/virology
Contents
xi
ANNUAL REVIEWS
It’s about time. Your time. It’s time well spent.
Now Available from Annual Reviews:
Annual Review of Virology
virology.annualreviews.org • Volume 1 • September 2014
Annual Review of Virology 2014.1:89-109. Downloaded from www.annualreviews.org
Access provided by 45.16.157.220 on 10/02/15. For personal use only.
Editor: Lynn W. Enquist, Princeton University
The Annual Review of Virology captures and communicates exciting advances in our understanding of viruses
of animals, plants, bacteria, archaea, fungi, and protozoa. Reviews highlight new ideas and directions in basic
virology, viral disease mechanisms, virus-host interactions, and cellular and immune responses to virus infection,
and reinforce the position of viruses as uniquely powerful probes of cellular function.
Complimentary online access to the first volume will be available until September 2015.
TABLE OF CONTENTS:
• Forty Years with Emerging Viruses, C.J. Peters
• Inventing Viruses, William C. Summers
• PHIRE and TWiV: Experiences in Bringing Virology to New Audiences,
Graham F. Hatfull, Vincent Racaniello
• Viruses and the Microbiota, Christopher M. Robinson, Julie K. Pfeiffer
• Role of the Vector in Arbovirus Transmission, Michael J. Conway,
Tonya M. Colpitts, Erol Fikrig
• Balance and Stealth: The Role of Noncoding RNAs in the Regulation
of Virus Gene Expression, Jennifer E. Cox, Christopher S. Sullivan
• Thinking Outside the Triangle: Replication Fidelity of the Largest RNA
Viruses, Everett Clinton Smith, Nicole R. Sexton, Mark R. Denison
• The Placenta as a Barrier to Viral Infections,
Elizabeth Delorme-Axford, Yoel Sadovsky, Carolyn B. Coyne
• Cytoplasmic RNA Granules and Viral Infection, Wei-Chih Tsai,
Richard E. Lloyd
• Mechanisms of Virus Membrane Fusion Proteins, Margaret Kielian
• Oncolytic Poxviruses, Winnie M. Chan, Grant McFadden
• Herpesvirus Genome Integration into Telomeric Repeats of Host
Cell Chromosomes, Nikolaus Osterrieder, Nina Wallaschek,
Benedikt B. Kaufer
• Viral Manipulation of Plant Host Membranes, Jean-François Laliberté,
Huanquan Zheng
• IFITM-Family Proteins: The Cell’s First Line of Antiviral Defense,
Charles C. Bailey, Guocai Zhong, I-Chueh Huang, Michael Farzan
• Glycan Engagement by Viruses: Receptor Switches and Specificity,
Luisa J. Ströh, Thilo Stehle
• Remarkable Mechanisms in Microbes to Resist Phage Infections,
Ron L. Dy, Corinna Richter, George P.C. Salmond, Peter C. Fineran
• Polydnaviruses: Nature’s Genetic Engineers, Michael R. Strand,
Gaelen R. Burke
• Human Cytomegalovirus: Coordinating Cellular Stress, Signaling,
and Metabolic Pathways, Thomas Shenk, James C. Alwine
• Vaccine Development as a Means to Control Dengue Virus
Pathogenesis: Do We Know Enough? Theodore C. Pierson,
Michael S. Diamond
• Archaeal Viruses: Diversity, Replication, and Structure, Nikki Dellas,
Jamie C. Snyder, Benjamin Bolduc, Mark J. Young
• AAV-Mediated Gene Therapy for Research and Therapeutic Purposes,
R. Jude Samulski, Nicholas Muzyczka
• Three-Dimensional Imaging of Viral Infections, Cristina Risco,
Isabel Fernández de Castro, Laura Sanz-Sánchez, Kedar Narayan,
Giovanna Grandinetti, Sriram Subramaniam
• New Methods in Tissue Engineering: Improved Models for Viral
Infection, Vyas Ramanan, Margaret A. Scull, Timothy P. Sheahan,
Charles M. Rice, Sangeeta N. Bhatia
• Live Cell Imaging of Retroviral Entry, Amy E. Hulme, Thomas J. Hope
• Parvoviruses: Small Does Not Mean Simple, Susan F. Cotmore,
Peter Tattersall
• Naked Viruses That Aren’t Always Naked: Quasi-Enveloped Agents
of Acute Hepatitis, Zongdi Feng, Asuka Hirai-Yuki, Kevin L. McKnight,
Stanley M. Lemon
• In Vitro Assembly of Retroviruses, Di L. Bush, Volker M. Vogt
• The Impact of Mass Spectrometry–Based Proteomics on Fundamental
Discoveries in Virology, Todd M. Greco, Benjamin A. Diner,
Ileana M. Cristea
• Viruses and the DNA Damage Response: Activation and Antagonism,
Micah A. Luftig
ANNUAL REVIEWS | Connect With Our Experts
Tel: 800.523.8635 (us/can) | Tel: 650.493.4400 | Fax: 650.424.0910 | Email: [email protected]