Interferons and viral infections
Volker Fensterl and Ganes C. Sen*
Department of Molecular Genetics, The Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
Abstract.
Interferons represent a family of cytokines, which is of
central importance in the innate immune response to virus
infections. All interferons act as secreted ligands of specific
cell surface receptors, eliciting the transcription of hundreds
of interferon-stimulated genes whose protein products have
antiviral activity, as well as antimicrobial, antiproliferative/
antitumor, and immunomodulatory effects. Expression of
type I and III interferons is induced in virtually all cell types
upon recognition of viral molecular patterns, especially
nucleic acids, by cytoplasmic and endosomal receptors,
whereas type II interferon is induced by cytokines such as
V
C 2009 International Union of Biochemistry and Molecular Biology, Inc.
Volume 35, Number 1, January/February 2009, Pages 14–20

E-mail: seng@ccf.org
1. The interferon family and
their receptors
In 1957, Isaacs and Lindenmann described a secreted macro-
molecule, which was produced by cells after treatment with
heat-inactivated influenza virus. The molecule was able to
‘‘interfere’’ with live virus replication and was therefore
termed interferon [1]. In the following five decades, the
human and murine interferon systems have been studied in
great detail, revealing the mechanisms of transcriptional
induction of interferon (IFN), its mode of action, its antiviral
and other effects, the numerous viral countermeasures, and
its benefits in clinical use.
Interferons are cytokines, which are produced in
response to viral and microbial infections, their most out-
standing characteristic being the ability to nonspecifically in-
hibit viral growth by inducing an ‘‘antiviral state’’ in cells.
Interferons consist of 165–208 amino acids in human, and
many are posttranslationally modified by glycosylation [2,3].
Interferon genes were cloned from mammals, birds, and
fish, and there are hints for interferon-like activity in
amphibians [4]. The mammalian interferons are divided into
*Address for correspondence: Ganes C. Sen, Ph.D., Department of Molecular Genetics/
NE20, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Tel: þ216 444
0636; Fax: þ216 444 0513; E-mail: seng@ccf.org.
Received 7 October 2008; accepted 7 November 2008
DOI: 10.1002/biof.6
Published online 2009 in Wiley InterScience
(www.interscience.wiley.com)
14
IL-12, and its expression is restricted to immune cells such
as T cells and NK cells. The effectiveness of the interferon
system in counteracting viral infections is reflected by the
multitude of inhibitors of interferon induction or interferon
action that are encoded by many viruses, preventing their
eradication and resulting in the continued coexistence of
viruses and vertebrates. The unique biological functions of
interferons have led to their therapeutic use in the
treatment of diseases such as hepatitis, multiple sclerosis,
and certain leukemias.
Keywords: Interferon, virus, antiviral, innate immunity
three types, based on amino acid sequence homology and
the receptors they use (Table 1): Type I IFN mainly refers to
the numerous subtypes of IFN-a (13 in human), and a single
IFN-b, all of which can be induced in most cell types, and
whose genes are arranged in a cluster on human chromo-
some 9. In addition, IFN-x, IFN-e, IFN-j, IFN-s, and IFN-f (¼
limitin) belong to the type I IFNs, but they are expressed
with cell-type and species specificity. For example, IFN-s is
expressed by trophoblasts and has been found in ruminants
only, whereas the limitins have been identified only in
mouse. All type I IFNs use the heterodimeric IFN-a/b recep-
tor (IFNAR). The only member of type II IFNs, IFN-c, is unre-
lated to type I IFN and engages the heterodimeric IFN-c re-
ceptor (IFNGR); it is mainly produced by activated T cells
and NK cells and its gene is located on human chromosome
12 [2,3,5]. The more recently identified group of type III IFNs
comprises IFN-k1, 2, and 3, also known as Interleukin-29 (IL-
29), IL-28A, and IL-28B, respectively. They engage the dis-
tinct heterodimeric IFN-k receptor IL10R2/IFNLR1 (Table 1)
and their genes are clustered on human chromosome 19.
Similarly to type I IFN, their inducibility by virus infection
appears to be ubiquitous [6].
2. The induction of
interferon synthesis
Viral infections result in the generation of pathogen-associ-
ated molecular patterns (PAMP), which, as a means of
sensing the presence of virus, can be recognized by pattern
 Table 1
Major components of the IFN signaling system

Type I IFN Type II IFN Type III IFN

Members IFN-a (13 subtypes) IFN-c (active as dimer) IFN-k1 (¼ IL-29)

IFN-b IFN-k2 (¼ IL-28A)
IFN-x IFN-k3 (¼ IL-28B)
IFN-e
IFN-j
IFN-d (pigs)
IFN-s (ruminants)
IFN-f/Limitin (mouse)
Receptors IFNAR1/IFNAR2c IFNGR1/IFNGR2, active as IL10R2 (¼ IL-10Rb)/IFNLR1
heterodimer two heterodimers (¼ IL-28Ra) heterodimer
Receptor-associated kinases JAK1, TYK2 JAK1, JAK2 JAK1, TYK2
Activated transcription factors ISGF3 (STAT1/STAT2/IRF-9) GAF (STAT1 homodimer) ISGF3 (STAT1/STAT2/IRF-9)
DNA binding sites ISRE GAS ISRE

recognition receptors (PRR) on the cell-surface, in the cyto-
plasm, or in endosomes. Interestingly, in most cases, the
ligands of these type I IFN-inducing receptors are viral
nucleic acids such as single-stranded (ss)RNA, double-
stranded (ds)DNA or dsRNA, or their synthetic analogs (see
Fig. 1) [7,8].
Figure 2 depicts a simplified view on PAMP-stimulated
interferon induction with the example of dsRNA-activated
signaling pathways. DsRNA representing viral RNA genomes
or viral replication intermediates can be sensed in the cyto-
plasm or in endosomes by the related cytoplasmic RNA heli-
cases RIG-I (retinoic acid-induced gene-I) and MDA-5 (mela-
noma differentiation-associated gene-5) [9–11]. Both RIG-I
and MDA-5 utilize the mitochondrial adaptor protein MAVS
(also known as IPS-1, VISA, or Cardif ) [12–15], which serves
as a platform for the initiation of signaling cascades. One
signaling branch, via a TRAF3-containing complex, activates
the closely related kinases TBK1 and IKKe, who are crucial
for the induction of type I (and type III) IFN in most cell
types, since they phosphorylate and activate the critical tran-
scription factors IRF-3 and IRF-7 [16–18]. The other signaling
branch starting from MAVS involves a TRAF6-containing com-
plex, which mediates activation of the three kinases IKK (IjB
kinase), p38, and JNK (c-JUN N-terminal kinase), terminally
resulting in the phosphorylation and activation of transcrip-
tion factors NF-jB, ATF-2, and c-JUN, respectively [14,15,19].
The endosomal detection or dsRNA requires TLR3 (Fig. 2),
whose dimerization allows for recruitment of the cytoplasmic
adapter protein TRIF (TIR domain-containing adaptor induc-
ing IFN-b). The consequent steps are quite similar to the
RIG-I-dependent pathways described earlier [20,21]. The
dsRNA-activated transcription factors bind to their respective
DNA elements in the promoters of type I and III IFNs as well
as other cytokine/chemokine genes, such as CXCL10 (IP-10)
and CCL5 (RANTES), and activate their transcription
[6,22,23].
The induction of IFN-a subtypes requires the inter-
feron-induced IRF-7, whereas IFN-b can be induced without
IRF-7 by the constitutively expressed IRF-3 (in concert with
NF-jB and ATF-2/c-JUN). Thus, a positive feedback of type I

Fig. 1. Ligands of type I IFN-inducing pattern recognition receptors. Viral pathogen-associated molecular patterns
(PAMP) or their synthetic analogs serve as ligands for toll-like receptors (TLR) in endosomes and on the cell-surface,
and for the cytoplasmic receptors RIG-I, MDA-5, and DAI, resulting in the induction of interferon synthesis.

Interferons and Viral Infections 15

 Fig. 2. Pathways of interferon induction and interferon signaling. Signaling events leading to the transcription of
interferon genes, elicited by double-stranded RNA present in the cytoplasm or in endosomes. The secreted type I
interferon subsequently acts via its cell-surface receptor, activating the ‘‘JAK-STAT pathway’’ and inducing the
expression of interferon-stimulated genes (ISG).

IFN induction takes place, for example, in fibroblasts, where
IFN-b induces IRF-7 in an autocrine manner, thereby driving
expression of numerous IFN-as [24]. However, the plasmacy-
toid dendritic cells (pDC) express IRF-7 constitutively and
are therefore able to immediately express IFN-as upon rec-
ognition of viral PAMPs, using TLR7/8 and TLR9 as recep-
tors. Furthermore, the pDCs are by far the major producer of
type I IFN in reaction to viral infections in vivo [25].
Type II (IFN-c) production does not occur in direct
response to viral PAMPs, but is stimulated by IL-12 and IL-
18, which are cytokines released by activated macrophages.
Accordingly, IFN-c production is delayed when compared
with type I IFN. IFN-c induction requires transcription factors
NF-jB and AP-1 in addition to cell-specific transcription fac-
tors such as NFAT (nuclear factor of activated T cells),
explaining its restriction to NK cells or activated T cells [26].
3. Interferon-activated signaling:
Janus kinase/signal transducer and
activator of transcription pathways
All interferons exert their effects by binding to specific ubiq-
uitously expressed cell-surface receptors, leading to the acti-
vation of signaling pathways which target the induction of a
large number of interferon-stimulated genes (ISG), whose
encoded proteins mediate the antiviral and other effects of
interferons. The classical components of the interferon-
dependent ‘‘JAK-STAT pathways’’ are listed in Table 1. The
monomeric type I IFN acts by assembling and engaging the
heterodimeric receptor IFNAR1/IFNAR2c (Fig. 2). The recep-
tor-associated Janus tyrosine kinases TYK2 and JAK1 then
phosphorylate each other as well as the transcription factors
STAT1 and STAT2 (signal transducer and activator of

16 BioFactors
transcription). The activated STATs form a heterodimer, asso-
ciate with IRF-9, and the ternary complex termed ISGF3 (ISG
factor 3) translocates into the nucleus and transactivates
ISGs by binding to the interferon-stimulated response ele-
ment (ISRE) in the promoter of ISGs [27]. According to the
current knowledge, type III IFNs, although using a different
receptor (Table 1), activate ISGF3 similarly to type I IFN [6].
Type II IFN-mediated STAT1 activation occurs after bind-
ing of the dimeric IFN-c to IFNGR1, resulting in a complex
that is stabilized by IFNGR2. The associated JAK1 and JAK2
phosphorylate and activate STAT1, which homodimerizes to
form the gamma-activated factor (GAF), which in the nucleus
binds to the gamma-activated site (GAS) in the promoters of
ISGs [27]. Since in type I IFN signaling, STAT1 homodimers
are formed to a minor degree as well, the sets of genes
induced by type I or II IFNs overlap partially [28]. In fact,
interferon-mediated gene induction is much more complex
than initially assumed. The other members of the STAT fam-
ily, STAT3, 4, 5A/B, and 6, which are predominantly activated
by other cytokines (e.g., IL-4 activates STAT6), are activated
to a minor extent by interferons as well. Furthermore, un-
phosphorylated STATs (U-STAT) play important roles in tran-
scriptional regulation of genes [29–31].
Importantly, numerous ISRE-driven genes can be
directly induced by virus-activated IRF-3 due to sequence-
similarity of IRF elements and ISREs, thus providing a
‘‘shortcut’’ to ISG induction as a means of an immediate
early antiviral response in infected cells [22,23].
After their initial discovery as key components of inter-
feron signaling, a total of four JAK and seven STAT family
proteins have been identified and recognized as components
of major signaling pathways used by more than 30 cytokine-,
growth factor-, and peptide receptors [32,33].
4. Interferon-stimulated genes as
effectors of IFN action
Interferons are defined by their antiviral effectiveness: on
one hand, viruses can be eliminated from infected cells, and
on the other hand, uninfected cells can develop an ‘‘antiviral
state,’’ both upon interferon exposure. Usually, ISGs do not
have virus-specificity, and therefore, replication of different
viruses can be inhibited by the actions of the same ISG, of-
ten in concert with several other ISGs. Analyses of antiviral
ISG functions include overexpression in infected cell cul-
tures, gene knock-out mouse models, and the identification
of virus-encoded inhibitors (see later).
The dsRNA-activated protein kinase, PKR, is induced by
interferon, although in many cell types, it is constitutively
expressed at low levels. Its activation occurs after binding to
(usually virus-derived) dsRNA, inducing its dimerization and
autophosphorylation. As a mechanism of action, PKR phos-
phorylates translation initiation factor 2a (eIF2a), which
results in cellular and viral translation inhibition [34,35]. The
protein activator of PKR, PACT, can also activate PKR by
direct binding in response to cellular stress, inducing apo-
ptosis [36,37]. PKR inhibits replication of mostly RNA viruses
Interferons and Viral Infections
such as Vesicular stomatitis virus (VSV), Encephalomyocardi-
tis virus (EMCV), West Nile virus (WNV), hepatitis C virus
(HCV), and DNA viruses such as Herpes simplex virus 1
(HSV-1) [35]. Another group of IFN-induced enzymes, which
needs dsRNA for its activation, are the 20 -50 -Oligoadenylate
synthetases which, upon binding dsRNA, generate unique 20 -
50 -linked AMP-oligomers (2-5A) from ATP. These 2-5As acti-
vate the latent RNase L, which dimerizes and cleaves cellular
and viral ssRNA, thereby inhibiting protein expression and
occasionally inducing apoptosis [3,35,38]. The OAS/RNase L
system is a major antiviral effector against picornaviruses
(EMCV) and influenza A virus, as well as other RNA viruses.
Depending on the nature of the virus, its genomic RNA or vi-
ral mRNAs are cleaved [38]. Furthermore, RNase L-cleaved
cellular RNAs can amplify interferon induction by serving as
ligands for RIG-I [39]. Nonspecific ssRNA cleavage also
occurs after induction of ISG20, a 30 -exoribonuclease, which
contributes to inhibition of RNA viruses such as VSV [40]. An
additional, nonenzymatic mechanism of translation inhibition
is pursued by the ISG56/IFIT family proteins P56 and P54 via
binding to eIF3, with human P56 acting against HCV [41–43].
Another IFN-induced protein, human MxA, accumulates at
cellular membranes around the nucleus, binds to viral nu-
cleocapsids, and inhibits viral intracellular trafficking. It is a
key component in innate defense against orthomyxoviruses
such as influenza virus, and additionally, it inhibits Measles
virus, VSV, Hantavirus, and Semliki Forest virus, but interest-
ingly not EMCV. Moreover, it is capable of inhibiting influ-
enza virus replication by binding to a viral RNA polymerase
subunit [35,44]. ISG15 is conjugated to target proteins by
interferon-inducible conjugases/ligases, a process similar to
ubiquitin conjugation; however, the effects of ISG15 conjuga-
tion are still unclear, although they contribute to HSV-1 and
influenza virus resistance [35]. Viperin (CIG5) might interfere
with viral budding of enveloped viruses such as human Cyto-
megalovirus (HCMV), HCV, and influenza virus by disrupting
lipid rafts in membranes, but its mode of action remains to
be determined [45]. The nucleic acid-editing enzymes APO-
BEC3G and -3F, representing deoxycytidine deaminases, in-
hibit retroviruses; they act by introducing C to U mutations
in viral reverse transcribed DNA or by directly interfering
with reverse transcription [46]. Apart from the many antiviral
effectors, signaling components such as RIG-I, TLR3, DAI,
IRF-7, and STAT1 are upregulated by interferons as well,
increasing the sensitivity of cells toward PAMPs.
Antibacterial effects of IFN are not clearly defined, but
imply the action of iNOS (inducible nitric oxide synthase)
especially in macrophages. iNOS catalyzes the oxidation of


L-arginine, generating the reactive intermediate NO , which
plays important roles in killing of bacteria, for example,
Mycobacterium and Salmonella [47].
Broader effects of interferons include immunomodula-
tory functions. IFN-a/b contributes to DC and macrophage
activation and the upregulation of MHC I molecules, whereas
IFN-c is important for promoting the transition from innate
to adaptive immune responses, for example, by inducing the
transcription factors IRF-1 and CIITA, which governs MHC II
expression. MHC II allows for antigen presentation to T
17
 Table 2
Viral inhibitors of the IFN system

Target level Target Virus (viral protein) Effect

IFN induction dsRNA Vaccinia virus (E3L) sequestration of dsRNA

Influenza A virus (NS1) sequestration of dsRNA
Ebolavirus (VP35) sequestration of dsRNA
MDA-5 Paramyxoviruses (V) binding/inhibition of MDA-5
MAVS Hepatitis C virus (NS3/4A) degradation of MAVS
Hepatitis A virus (3ABC) degradation of MAVS
TRIF Hepatitis C virus (NS3/4A) degradation of TRIF
TBK1 Borna disease virus (P) pseudosubstrate for TBK1
New York-1 virus (Gn) prevents TRAF3 interaction
IKKe, TBK1 Mumps virus, Parainfluenzavirus 5 (V) pseudosubstrates, degradation of IKKe/TBK1
IRF-3 Rotavirus (NSP1) IRF-3 binding/degradation
Human papillomavirus 16 (E6) IRF-3 binding/inhibition
Rabies virus (P) prevents IRF-3 phosphorylation
IFN signaling Secreted IFN Poxviruses (soluble IFN-binding proteins) sequestration of IFN
JAKs Human Cytomegalovirus loss of JAK1, IRF-9
Human papillomavirus 18 (E6) binds/inhibits TYK2
STATs Paramyxoviruses loss/sequestration of STATs
Rabies virus (P) STAT1/2 binding/inhibition
Adenovirus (E1A) loss of STAT1, IRF-9
Human Cytomegalovirus (IE1-72kDa) prevents ISGF3 DNA binding
Ebolavirus inhibits STAT trafficking
ISG protein function PKR Influenza A virus (NS1) binding/inhibition of PKR
Hepatitis C virus (NS5A, E2) binding/inhibition of PKR
Adenovirus (VA-RNA) inhibits dimerization of PKR
ISG15 Influenza B virus (NS1) inhibits ISG15 conjugation
Crimean Congo hemorrhagic virus (L) de-ISG15ylation of proteins

helper cells, whose differentiation to Th1 cells is driven by
IFN-c. At the same time, IFN-c represents the marker cyto-
kine of activated Th1 cells during the adaptive immune
response. Furthermore, IFN-c regulates NK and B cell func-
tions as well as macrophage activation, the latter playing
critical roles in the microbicidal effects of IFN-c (rather than
IFN-a/b) [48,49].
Important insights into both the function and specific-
ity of many components of the interferon system described
earlier were obtained from murine gene knock-out studies.
Usually, a gene deficiency for a critical component renders
the animal very susceptible to virus infections, increasing
morbidity and/or mortality, as seen with IFN-b, IFNAR,
IFNGR, MAVS, IRF-3, or IRF-7 knock-out mice [50–54]. Simi-
larly, naturally occurring, rare mutations in human genes can
result in functional deficiency of the gene. For instance,
TYK2 deficiency leads to enhanced susceptibility to infection
by viruses, fungi, and mycobacteria [55]. Interestingly, mono-
genic deficiencies were found to be linked to development
of Herpes simplex virus encephalitis (HSE), as seen in
patients with deficiencies for STAT1 or UNC93B1, which is a
protein critically involved in directing TLR3/7/9 to endolyso-
somes for signaling [56]. Indeed, HSE and human TLR3 defi-
ciency could be connected as well, pointing to a protective
role for TLR3 and interferon signaling in the central nervous
system [57].
5. Viral evasion strategies
The importance of the interferon system is reflected by the
large number of inhibitors or modulators encoded by most,
if not all, viruses. Table 2 gives a few examples of the diver-
sity of viral inhibitors; for a comprehensive review, the
reader is referred to ref. [45]. The inhibitory mechanisms
include interruptions on the levels of IFN induction, IFN sig-
naling, and ISG protein functions. Induction can be inhibited
by sequestration or masking of dsRNA, binding to MDA-5,
degradation of MAVS or TRIF, forming pseudosubstrates for
the kinases TBK1/IKKe, or by interfering with IRF-3 function
directly. Similarly, IFN signaling can be inhibited by viruses
by inducing degradation of JAK-STAT pathway components or
by neutralizing IFNs with soluble viral IFN receptors. Several
viral inhibitors even target ISG proteins such as PKR [45,58–
61]. Although most viruses encode one or more inhibitory
proteins, they can still induce interferon and can be inhibited
by interferon treatment, emphasizing the evolutionary bal-
ance between the virus and the host.

18 BioFactors

6. Clinical use of interferons
The antiviral and immunomodulatory effects of interferons
have led to their use as therapeutics. Treatments of a num-
ber of viral and nonviral diseases currently include recombi-
nant interferons. IFN-a2 is administered to patients chroni-
cally infected with hepatitis C virus and hepatitis B virus.
IFN-b is commonly used in treatment of relapsing-remitting
multiple sclerosis (MS) because of its beneficial effects. The
pathogenesis of MS remains largely unknown, and so are
the reasons for the effectiveness of IFN-b [62,63]. Proapop-
totic and cytostatic functions have been ascribed to interfer-
ons, leading to apoptosis of certain tumor cell types and
size reduction of tumors, as well as inhibition of angiogene-
sis in vivo [63]. The underlying mechanisms are not fully
understood. For example, PKR and the apoptosis-inducing
ligand TRAIL have been implicated in apoptotic responses to
interferons, whereas IFI-16, a member of the p200 family of
ISGs, has been related to antiproliferative effects, as it inter-
acts with several transcription factors, such as p53, pRb, and
E2F, and inhibits their functions [45,64]. Accordingly, interfer-
ons have been used for the treatment of several types of
cancer such as certain leukemias, lymphoma, malignant mel-
anoma, multiple myeloma, renal cell carcinoma, and Kaposi’s
sarcoma [62,65].
7. Conclusions
Interferons are essential for the immediate nonspecific host
defense against many viruses and promote the onset of an
adaptive immune response. Their antiviral, immunomodula-
tory, and antitumor effects make them effective therapeutics
for clinical use; however, future research will be needed to
help understand the underlying mechanisms of their effects
and side-effects in order to take full advantage of their ther-
apeutic potential.
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