The Dynamic Interface of Viruses with STATs

Viruses commonly antagonize the antiviral type I interferon response by targeting signal transducer and activator of transcription 1 (STAT1) and STAT2, key mediators of interferon signaling. Other STAT family members mediate signaling by diverse cytokines important to infection, but their relationship with viruses is more complex. Importantly, virus-STAT interaction can be antagonistic or stimulatory depending on diverse viral and cellular factors. While STAT antagonism can suppress immune pathways, many viruses promote activation of specific STATs to support viral gene expression and/or produce cellular conditions conducive to infection.

ABSTRACT

Viruses commonly antagonize the antiviral type I interferon response by targeting signal transducer and activator of transcription 1 (STAT1) and STAT2, key mediators of interferon signaling. Other STAT family members mediate signaling by diverse cytokines important to infection, but their relationship with viruses is more complex. Importantly, virus-STAT interaction can be antagonistic or stimulatory depending on diverse viral and cellular factors. While STAT antagonism can suppress immune pathways, many viruses promote activation of specific STATs to support viral gene expression and/or produce cellular conditions conducive to infection. It is also becoming increasingly clear that viruses can hijack noncanonical STAT functions to benefit infection. For a number of viruses, STAT function is dynamically modulated through infection as requirements for replication change. Given the critical role of STATs in infection by diverse viruses, the virus-STAT interface is an attractive target for the development of antivirals and live-attenuated viral vaccines. Here, we review current understanding of the complex and dynamic virus-STAT interface and discuss how this relationship might be harnessed for medical applications.

THE JAK-STAT PATHWAY

The antiviral immune response requires an array of cytokines and chemokines, many of which signal through STATs (Table 1). The STAT family has seven members in mammals—STAT1 to -4, STAT5a, STAT5b, and STAT6—which share common structural domains that mediate intracellular signaling (Fig. 1A) (1). In the canonical Janus kinase (JAK)-STAT pathway, STATs are activated by receptor-associated kinases of the JAK family (comprising JAK1 to -3 and Tyk2) that undergo autophosphorylation following binding of cytokines, growth factors, etc., to cognate receptors (Fig. 1B) (1, 2). Latent STATs are recruited to receptors and phosphorylated at a conserved tyrosine (pY) by JAKs, resulting in formation of parallel pY-STAT dimers through reciprocal interactions of the pY and Src homology 2 (SH2) domains. The dimers accumulate in the nucleus and bind specific promoter elements to regulate the transcription of large numbers of target genes. Signaling is then deactivated by protein tyrosine phosphatases (PTPs) and members of the protein inhibitor of activated STAT (PIAS) and suppressor of cytokine signaling (SOCS) families (Fig. 1B) (1–3). STATs are further regulated by posttranslational modifications (PTMs) that enhance or inhibit signaling, including serine phosphorylation, acetylation, methylation, sumoylation, and ISGylation (2, 3).

TABLE 1.

Examples of STAT activators and heterodimer partners

STAT	Principal activator(s)a	Heterodimer partners/cytokines shown to promote heterodimer formation	References
STAT1	All IFNs	STAT2 (type I and III IFNs) STAT3 (IFNs, IL-6, IL-27, EGF) STAT4 (IL-35)	1, 4, 25, 216
STAT2	Type I and III IFNs	STAT1 (type I and III IFNs) STAT6 (type I IFNs)	1, 4
STAT3	IL-6 family (e.g., IL-6, LIF, OSM) IL-10, G-CSF, EGF	STAT1 (IFNs, IL-6, IL-27, EGF) STAT5 (IL-2, IL-7 M-CSF, PDGF) STAT4 (IL-23)	1, 4, 25, 151, 216
STAT4	IL-12, IL-23, IL-35	STAT1 (IL-35) STAT3 (IL-23)	1, 4
STAT5a/b	Gamma chain cytokine family (e.g. IL-2, IL-7, IL-15) IL-3, GM-CSF, prolactin, EPO	STAT3 (IL-2, IL-7 M-CSF, PDGF)	1, 4, 97, 151
STAT6	IL-4, IL-13, IL-15, PDGF	STAT2 (type I IFNs)	1, 4, 126

^aEGF, epidermal growth factor; PDGF, platelet-derived growth factor.

FIG 1.

Structure and signaling pathways of STATs. (A) Schematic representation of the conserved domain structure of STATs: N-terminal domain (ND), coiled-coil domain (CCD), DNA-binding domain (DBD), linker domain, Src homology 2 (SH2) domain, and C-terminal transactivation domain (TAD). The conserved C-terminal tyrosine phosphorylated by JAKs (pY) is indicated. (B) Diverse cytokines signal via a classical JAK-STAT paradigm. (1 and 2) Cytokine, growth factor, etc., bind to the cognate receptor (1), activating specific receptor-associated JAKs (2). (3) JAKs phosphorylate latent antiparallel STAT dimers (P in circles), inducing the formation of parallel dimers through reciprocal pY-SH2 interactions. (4) pY-STAT dimers translocate into the nucleus and bind specific DNA elements, activating gene expression. (5) pY-STATs are dephosphorylated by nuclear and cytoplasmic PTPs to turn off signaling. (6 and 7) STAT signaling is also negatively regulated (blunt arrows) by PIAS proteins (which bind STATs and prevent DNA binding, recruit corepressors, or mediate sumoylation) (6) and SOCS proteins (which are induced by pY-STATs and inhibit JAK kinase activity, bind competitively to STAT-binding sites on receptors, or target cytokine receptors and JAKs for proteasomal degradation; dotted line) (7). Red line, negative regulation; black line, positive regulation. (8) STATs are also positively or negatively regulated by PTMs.

Cytokine-specific transcriptional responses derive from the activation of specific subsets of STATs by different cytokines due to interactions of receptors with specific JAKs and STATs (1); this induces an array of STAT homo- and heterodimers (Table 1) (4). Viral targeting of specific STATs and/or STAT complexes can thus have major impacts on cell biology and immunity.

STAT1/2 ARE COMMON VIRAL TARGETS

The interferon (IFN) response is the principal line of defense of mammalian cells against viral infection (3, 5). Type I (e.g., IFN-α and IFN-β), type II (IFN-γ), and type III (e.g., IFN-λ1) IFNs are produced by immune and nonimmune cells following detection of virus and/or infection and signal in autocrine and paracrine fashion by binding to broadly expressed receptors to activate STAT1 or STAT1 and -2. Type I and III IFNs primarily activate STAT1-STAT2 heterodimers, which, with IFN regulatory factor 9 (IRF-9), form the IFN-stimulated gene factor 3 (ISGF3) complex and bind genomic IFN-stimulated response elements (ISREs). Type II IFNs primarily activate STAT1 homodimers that bind gamma-activated sequence (GAS) elements. ISRE/GAS sequences regulate the transcription of hundreds of IFN-stimulated genes (ISGs), many of which encode proteins with antiviral, antiproliferative, proapoptotic, or immune-modulatory functions to suppress viral replication and promote adaptive responses (5).

To prosper within cells, viruses must counteract IFN responses. This is commonly mediated by viral IFN antagonist proteins, hundreds of which have been described. Among them, antagonists of STAT1 and/or -2 are common (reviewed in references 3, 5, and 6), with effector mechanisms that include cytoplasmic sequestration, dephosphorylation, or degradation of STATs; inhibition of upstream signaling components; and induction of negative regulators (Table 2). Notably, a number of viruses show selective targeting of STAT1 or STAT2, resulting in differential antagonism of IFN cytokines. Among paramyxoviruses, simian virus 5 V protein targets STAT1 and has broad impact on IFNs (7), while human parainfluenza virus 2 V protein preferentially antagonizes STAT2, thereby inhibiting type I and III but not type II IFNs (8–10). Similarly, Zika virus (ZIKV) NS5 mediates the degradation of STAT2, suppressing signaling by type I/III but not type II IFNs (11, 12). Notably, loss of STAT2 expression also promotes the formation of STAT1 homodimers, enhancing IFN-γ-induced ISG expression (13). Since IFN-γ positively affects ZIKV replication (13), STAT2 degradation may represent a mechanism to simultaneously suppress antiviral signaling while promoting proviral signaling. Thus, STAT1/2 targeting is a common strategy for antagonism and, potentially, modulation of innate immune responses.

TABLE 2.

Examples of STAT1/2-antagonistic strategies of viruses

Mechanism	Virus/IFN antagonista (reference)
Interaction of IFN antagonists with STAT1/2
Cytoplasmic sequestration	RABV P1 (187)
	NIV V (95)
	Huaiyangshan banyangvirus NSs (217)
Inhibition of DNA binding	HCMV IE1 (218)
	RABV P (153, 214)
	Porcine bocavirus NP1 (219)
Dephosphorylation of STATs	Vaccinia virus VH1 (220)
Inhibition of ISGF3 complex formation	MEV V (221)
Targeting of STATs for proteasomal degradation	Simian virus 5 V (222)
	Dengue virus NS5 (223)
	ZIKV NS5 (11, 12)
	PEDV (224)
Indirect antagonism
Inhibition of transcription from STAT gene	HPV E6/E7 (225)
Inhibition of STAT nuclear import machinery	Ebola virus VP24 (226)
	HBV Pol (227)
	PRRSV Nsp1β (228)
Reduced IFN receptor expression	Respiratory syncytial virus NS1 (229)
	EBV LMP2A/B (230)
Inhibition of JAK expression/activity	Marburg virus VP40 (231)
	EBV LMP1 (36)
	Murine polyomavirus T antigen (232)
	Adenovirus (233)
Upregulation of negative regulators of STAT	IAV NS1 (154)
	HBV X (234)
	HCV core (235)

^aPRRSV, porcine reproductive and respiratory syndrome virus.

STAT3: A PRO- AND ANTIVIRAL MOLECULE

STAT3 is a pleiotropic signaling molecule involved in processes including growth and development, consistent with embryonic lethality of STAT3-deficient mice (14, 15). STAT3 is generally considered a prosurvival or proliferation factor, consistent with association with many cancers (16), but also has proapoptotic roles (17, 18). STAT3 mediates signaling by diverse cytokines (Table 1), including as the major mediator of Gp130 receptor signaling by interleukin-6 (IL-6) family cytokines (1, 15). IL-6 cytokines are important to immunity, including the acute-phase inflammatory response, antibody production, and T-cell differentiation (19). Interestingly, STAT3 also mediates anti-inflammatory IL-10 signaling (1, 15).

STAT3 is also implicated in IFN responses, although its precise role is complicated by reports indicating distinct or opposing effects of STAT3 depletion. Specifically, some data indicate that STAT3 has antiviral activity as an important component of IFN signaling (20–24), while others indicate a negative regulatory role toward IFN (25–28). It has been suggested that this disparity might be due in part to the use of different cell types in the studies (21). Indeed, the diverse functions attributed to STAT3 likely derive to a great extent from distinct roles in different cell types, as genomic binding patterns of STAT3 are largely cell-type specific, relating to cell-specific interactions with coactivators and repressors (29, 30). Nevertheless, STAT3 binds and regulates a “universal” gene subset, independent of cell type (29, 30). Notably, STAT3 has also been reported to have opposing roles within the same cell type. For example, the STAT3-activating cytokines IL-6, IL-10, and IL-21 produce proinflammatory, anti-inflammatory, and proapoptotic outcomes, respectively, in dendritic cells (29, 31, 32). Thus, STAT3 function appears to be determined by several factors, potentially involving PTMs and heterodimerization with other STATs (4, 29).

VIRAL ACTIVATION OF STAT3

The relationship of STAT3 with viruses is complex, relating to the diversity of STAT3 functions and the diverse nature of viruses (33–35). Many oncoviruses promote STAT3 activation to upregulate prosurvival and proproliferation genes through direct interaction of viral proteins with STAT3 and/or activation of upstream signaling (Table 3). The Epstein-Barr virus (EBV) oncoprotein LMP1, which blocks STAT2 activation by IFN-α (36), promotes STAT3 activation and STAT3-dependent gene expression via upregulation of IL-6 (37, 38), highlighting the distinct and opposing roles that STATs can play in infection. Interestingly, the LMP1 promoter contains a STAT3-binding site and so is induced in response to STAT3-activating cytokines (Fig. 2A) (38–41). This appears to form a positive-feedback loop that promotes cellular transformation during infection (38, 39). The feedback loop likely also promotes latency, since STAT3 is implicated in maintaining latency of EBV and other herpesviruses (Kaposi’s sarcoma-associated herpesvirus [KSHV] and herpes simplex virus 1 [HSV-1]) by inducing the expression of host-encoded transcriptional repressors of lytic genes (42–45). Notably, the HSV-1 genome also contains STAT3-binding elements. During HSV-1 infection, STAT3 induces NEAT1, a noncoding cellular RNA involved in forming intranuclear paraspeckles. STAT3 is also recruited to the paraspeckles and interacts with the viral genome to induce expression of the HSV-1 ICP0 and TK genes (46). Thus, STAT3 appears to be an important proviral factor for multiple herpesviruses.

TABLE 3.

Examples of viral regulators of STAT3^a

Virus	Effect on STAT3	Reference(s)
EBV	EBV proteins LMP1, LMP2A, and EBNA2 upregulate STAT3 signaling to promote cell growth/transformation and viral gene expression/latency and inhibit autophagy. STAT3 binds and activates transcription from promoters of LMP1 and EBNA1 in the viral genome.	37–41, 73, 74, 236–239
HBV	HBV X protein promotes STAT3 activation through interaction with JAK1, deregulation of cellular miRNA expression, and induction of reactive oxygen species. HBV infection activates STAT3 through IL-6-dependent pathways. STAT3 activation impacts viral gene expression/replication, cell survival/proliferation, and apoptosis. STAT3 binds and activates transcription from enhancer 1 in the viral genome.	47–53
HPV	HPV E6 upregulates IL-6/STAT3 signaling to promote viral gene expression and tumorigenesis. STAT3 binds the upstream regulatory region in the viral genome.	240–243
Varicella-zoster virus	Varicella-zoster virus upregulates miR-21 to enhance STAT3 signaling, promoting cell survival and virus replication.	192, 244
Rift Valley fever virus	Rift Valley fever virus NSs induces STAT3 activation to promote cell survival and inhibit virus-induced cell death.	245
PEDV	PEDV upregulates EGFR/STAT3 signaling to inhibit type I IFN signaling and promote viral replication.	55
KSHV	KSHV upregulates STAT3 signaling, including through binding of KSHV LANA and RTA to STAT3 and through JAK-dependent pathways. KSHV kaposin B induces monophosphorylation of STAT3 at S727. STAT3 signaling promotes cell transformation, latency, and inflammatory responses and inhibits autophagy.	43, 75, 141–146, 181
	KSHV cyclin K binds STAT3 and inhibits growth-suppressive effects of OSM. KSHV encodes miRNAs that inhibit IL-6/IFN-α-induced STAT3 activation/target gene expression. STAT3 inhibition may induce lytic reactivation.	106, 246, 247
HCV	HCV upregulates STAT3 signaling, including through binding of HCV core to STAT3, upregulation of IL-6, and induction of reactive oxygen species. STAT3 activation deregulates inflammatory responses and promotes cell proliferation/transformation and viral replication.	63–68
	HCV blocks STAT3-DNA binding and induces proteasomal degradation of STAT3, inhibiting IFN-α/LIF signaling.	69, 70
HCMV	HCMV US28 upregulates IL-6/STAT3 signaling to promote cell proliferation/transformation. STAT3 activity is required for efficient viral gene expression/replication.	71, 193, 248
	HCMV IE1 binds and sequesters unphosphorylated STAT3 in the nucleus, inhibiting IL-6/STAT3-dependent gene expression and rewiring IL-6 signaling into an IFN-γ-like response. HCMV inhibits STAT3 activation in response to IFN-α/γ.	71, 72, 249
HIV-1	HIV-1 Nef and gp120 upregulate soluble factors that activate STAT3, potentially promoting cell survival and deregulating inflammatory responses. HIV-1 induces monophosphorylation of STAT3 at S727. HIV-1 upregulates IL-10/STAT3 signaling in bystander cells to inhibit autophagy.	76, 156, 180, 250
	HIV-1 Vif induces proteasomal degradation of STAT3, inhibiting IFN-α signaling.	251
EV71	EV71 induces STAT3 activation to inhibit type I IFN signaling and promote viral replication.	54
	EV71 induces miRNA-124, which suppresses IL-6/STAT3 signaling to inhibit anti-EV71 activity. EV71 induces proteasomal degradation of STAT3.	54, 252
RABV	RABV induces miRNA-455, which suppresses SOCS3 and enhances STAT3 activation to promote viral replication.	253
	RABV P protein selectively binds IFN-α/OSM-activated STAT3-STAT1 heterodimers to inhibit nuclear accumulation and target gene expression.	155, 189
IAV	IAV induces STAT3 activation to delay apoptosis.	254
	IAV inhibits STAT3 activation in response to IFN-β/IL-6 by upregulating SOCS3 and downregulating IFN receptor. Inhibition of IL-6/STAT3 signaling is associated with disease severity in vivo.	154, 255
Severe acute respiratory syndrome coronavirus 1	Severe acute respiratory syndrome coronavirus 1 PLpro promotes STAT3 signaling to upregulate the Egr-1/TGF-β1b fibrotic pathway.	256
	Severe acute respiratory syndrome coronavirus 1 reduces STAT3 phosphorylation, potentially promoting apoptosis.	257
MUV	MUV V protein induces proteasomal degradation of STAT3, inhibiting IL-6/v-Src/STAT3-dependent gene expression. STAT3 antagonism is associated with disease severity in vivo.	57, 59
MEV	MEV V protein binds STAT3, inhibiting IL-6/v-Src/STAT3-dependent gene expression.	58
Tioman virus	Tioman virus V protein binds STAT3, inhibiting IL-6/STAT3-dependent gene expression.	62
PRRSV	PRRSV NSP5 induces proteasomal degradation of STAT3, inhibiting OSM/STAT3-dependent gene expression.	258
Hepatitis E virus	Hepatitis E virus ORF3 disrupts EGF receptor trafficking, inhibiting EGF/STAT3-dependent gene expression.	259
Marburg virus	Marburg virus VP40 inhibits JAK1 phosphorylation, suppressing IL-6-induced STAT3 activation.	231
Human metapneumovirus	Human metapneumovirus inhibits JAK2 phosphorylation, suppressing IL-6/STAT3-dependent gene expression.	260
Adenovirus	Adenovirus inhibits JAK1 phosphorylation, suppressing IL-6/OSM-induced STAT3 activation.	233

^aLightface and boldface indicate stimulatory and inhibitory effects, respectively, on STAT3.

^bTGF-β1, transforming growth factor β1.

FIG 2.

Examples of viruses with genomic STAT-binding sites. (A) The EBV LMP1 promoter contains STAT3 and STAT6 sites. Cytokines activating STAT3 (IL-6, IL-21, and IL-10) or STAT6 (IL-13 and IL-4) induce LMP1, promoting cell transformation. LMP1 upregulates IL-6, resulting in a positive-feedback loop. EBV Zta protein induces IL-13, and IL-13 induces LMP1 via STAT6. (B) HBV enhancer 1 contains a STAT3 site. Cytokines activating STAT3 (IL-6 and epidermal growth factor [EGF]) induce viral gene expression. HBV (including HBV X protein) induces STAT3 activation. (C) The HIV-1 LTR contains a STAT5 site that is activated by STAT5-activating cytokines (e.g., IL-2, GM-CSF, IL-7, and IL-15) to induce gene expression and viral reactivation; this is inhibited in cells expressing C-terminally truncated STAT5, which binds to the LTR site. (D) The B19V replication origin in inverted terminal repeats (ITRs) contains a STAT5 site, where EPO/hypoxia-activated pY-STAT3 recruits the minichromosome maintenance (MCM) complex to initiate replication. (E) The KSHV RTA promoter contains a STAT6 site; LANA mediates cleavage of the STAT6 C terminus, and cleaved STAT6 binds to the RTA promoter, repressing RTA expression to promote latency. During lytic infection, expressed RTA induces STAT6 degradation.

Hepatitis B virus (HBV) also hijacks STAT3 to activate viral gene expression (Fig. 2B) (47) and, consistent with this, promotes STAT3 activation through several mechanisms (Table 3) (48–50). HBV-induced STAT3 activation also upregulates cellular genes, which appears to promote a prosurvival (49, 51) or proapoptotic (52, 53) state, depending on the cell type. Certain nononcogenic viruses also exploit STAT3 to promote cell survival (Table 3), while the reported capability of STAT3 to downregulate the antiviral IFN response (see above) appears to be hijacked by enterovirus 71 (EV71) (54) and porcine epidemic diarrhea virus (PEDV) (55). Clearly, STAT3 is an important proviral factor for diverse viruses, despite differences in the specific cellular outcomes of STAT3 activation.

VIRAL ANTAGONISM OF STAT3

Despite evident proviral activities, inhibition of STAT3 signaling also forms part of the immune evasion strategy of many viruses. The paramyxoviruses mumps virus (MUV) and measles virus (MEV) antagonize IFN/IL-6-dependent STAT signaling via the V protein; MUV V protein targets STAT3 and STAT1 for proteasomal degradation (56, 57), while MEV V protein binds STAT1, -2, and -3 and inhibits nuclear translocation (58). Disruption of STAT3 antagonism by mutation of MUV V protein reduced neurovirulence in vivo (59, 60), indicative of an important role in disease. Interestingly, V proteins of the paramyxoviruses Hendra virus, Nipah virus (NIV), and simian virus 5 target STAT1 and/or -2 but not STAT3 (57, 61), while Tioman bat paramyxovirus V protein does not target STAT1 or -2 but can bind STAT3 and impair IL-6 signaling (62). Thus, STAT3/IL-6 antagonism appears to have highly specific roles in the biology of certain paramyxoviruses. Precisely how the differential targeting of STATs impacts the transcriptome in response to specific cytokines and the consequences for host and viral biology are not resolved.

The list of viruses that antagonize STAT3 is growing in number and diversity (Table 3). Interestingly, while activation of STAT3 by hepatitis C virus (HCV) is well established (63–67), consistent with a proviral role (67, 68), STAT3 also has anti-HCV activity (24) and is inhibited or degraded during infection (69, 70). The reason for these apparently contrasting findings is unclear, but a number of viruses that can induce STAT3 signaling with apparently proviral effects also encode STAT3-antagonistic mechanisms (Table 3). In an interesting variation on this theme, human cytomegalovirus (HCMV) IE1 protein binds and sequesters unphosphorylated STAT3 within the nucleus, preventing activation and target gene expression in response to IL-6 (71). However, depletion or pharmacological inhibition of STAT3 impairs HCMV gene expression and replication, correlating with impaired nuclear relocalization. Thus, it seems that STAT3 nuclear sequestration is important for both immune evasion and HCMV replication (71). Notably, STAT3 antagonism by IE1 also results in enhanced activation of STAT1 in response to IL-6 cytokines, so that IE1 “rewires” IL-6 signaling into an IFN-γ-like response (72), similar to the modulation of STAT1/2 responses by ZIKV (see above).

The balance between activation and antagonism of STAT3 by different viruses, and even by the same virus, likely depends on a range of host and viral factors, including differing roles for STAT3 in different cell types and cytokine pathways, virus-specific requirements for infection (e.g., cell lysis to release progeny or promotion of cell survival to facilitate replication and reduce inflammation), and distinct requirements through stages of infection (e.g., early versus late and lytic versus latent). Indeed, for many viruses, different infection stages are characterized by expression of distinct viral protein subsets, which might have specific relationships with STAT3. Virus infection can also activate or regulate other cellular pathways (e.g., stress responses) that modulate STAT3-regulatory proteins or PTMs, potentially defining in dynamic fashion whether STAT3 is pro- or antiviral. For example, EBV, KSHV, and human immunodeficiency virus type 1 (HIV-1) induce STAT3 phosphorylation at serine 727 (S727) (73–76), which is required for maximal transactivation function (2). Despite these insights, it is clear that our understanding of the potentially nuanced and dynamic relationship of viruses and STAT3 is still in its infancy.

STAT4

STAT4 is the key mediator of signaling by IL-12, which is produced by a number of innate immune cells in response to infection (77). IL-12 primarily acts on natural killer (NK) and T cells to induce IFN-γ and other genes through STAT4, so that IL-12-induced activation of NK cells and differentiation of T helper 1 cells is impaired in STAT4-deficient mice (78, 79). STAT4 is also activated by other cytokines (Table 1), including type I IFNs that induce expression of IFN-γ (80–82) and specific ISGs (83, 84) via STAT4.

It is not surprising that STAT4 is implicated in antiviral immunity, including roles in IFN-γ induction and CD4⁺ and CD8⁺ T cell responses during lymphocytic choriomeningitis virus infection (80, 84–86), and in efficient NK cell responses to murine cytomegalovirus (87). Meta-analysis identified a link between a STAT4 polymorphism and chronic HBV infection (88). STAT4 was also implicated in effective IFN-γ responses to HSV-2 (89). However, for HSV-1 ocular infection, the importance of STAT4 is unclear, with one study indicating that STAT4-deficient mice are more susceptible to encephalitis and facial lesions (90) while another indicated no impact on disease severity, although higher viral titers were detected in the eyes of STAT4-deficient mice at early time points (91). STAT4-deficient mice could also mount T-cell and antibody responses against influenza A virus (IAV) as effectively as wild-type mice, resulting in viral clearance (92). Thus, the extent to which STAT4 contributes to immunity might be virus specific. Interestingly, a noncanonical role for unphosphorylated STAT4 in type I IFN induction in response to RNA viruses has been reported in macrophages. STAT4 interacts with the E3 ligase CHIP and inhibits CHIP-mediated proteasomal degradation of retinoic-acid-inducible gene I (RIG-I), promoting RIG-I-dependent IFN induction (93).

Despite apparent antiviral activities, evidence of direct viral antagonism of STAT4 is scarce, possibly reflecting restricted tissue distribution. However, STAT4 was recently identified as a binding partner of the NIV IFN antagonist protein isoforms V and W (94). Since V and W antagonize STAT1 by direct binding (95, 96) and mutation of V/W residue G121 disrupts binding to STAT1 and STAT4 (94), it seems likely that V/W-STAT4 interaction is antagonistic, affecting signaling by STAT4-activating cytokines. Confirmation of the role of this interaction awaits further investigation.

STAT5a/b

STAT5a and -b are highly homologous proteins that arose from gene duplication and function in overlapping and distinct processes as STAT5a/b homo- or heterodimers. STAT5a/b mediate signaling by multiple cytokines and growth factors (Table 1) and are implicated in growth; erythropoiesis; lymphoid development and differentiation; and proliferation and activity of myeloid, NK, and T cells (97). By mediating signaling by gamma chain cytokines, STAT5a/b have key roles in expansion and differentiation of T cells and enhancing the cytolytic activity of NK cells (98). STAT5a/b are also activated by and contribute to the antiviral IFN response (99–102).

In common with STAT3, STAT5 is associated with many cancers due to prosurvival and proliferation functions (97), including cancers caused by human T-lymphotropic virus type I (HTLV-1), EBV, and human papillomavirus (HPV) (Table 4). Moreover, the E7 protein of high-risk HPV promotes STAT5 activation to induce genes involved in DNA damage responses, which are required for viral genome replication in differentiating epithelial cells (103, 104). Similar to its relationship with STAT3, KSHV can promote and inhibit STAT5 pathways. Upregulation of the IL-3/STAT5 pathway to induce PROX1 expression is critical for KSHV reprogramming of blood vascular endothelial cell fate (105), while KSHV-encoded microRNAs (miRNAs) target erythropoietin (EPO) receptor mRNA in endothelial cells, downregulating EPO-dependent STAT5 signaling (106). These data are consistent with STAT5 being pro- or antiviral for KSHV, depending on the cellular and signaling context.

TABLE 4.

Examples of viral regulators of STAT5^a

Virus	Effect on STAT5	Reference(s)
EBV	EBV LMP1 upregulates STAT5 signaling to promote cell growth/transformation.	38, 39, 261
HTLV-1	HTLV-1 p12(I) and Tax upregulate STAT5 signaling to promote cell proliferation/transformation.	262–265
HPV	HPV upregulates STAT5 signaling to promote cell survival/proliferation and induce ATM/ATR DNA damage responses, promoting viral gene expression/replication. STAT5 binds the regulatory region in the viral genome.	103, 104, 266–269
B19V	STAT5 binds inverted terminal repeats in the viral genome, promoting B19V genome replication.	122, 123
KSHV	KSHV upregulates IL-3/STAT5 signaling to reprogram cell fate.	105
	KSHV encodes miRNAs that target EPO receptor mRNA, inhibiting EPO/STAT5 signaling.	106
HIV-1	HIV-1 increases basal STAT5 activation. Cytokine (e.g. IL-2, IL-15, and IL-7)-activated full-length or C-terminally truncated STAT5 binds LTRs in the viral genome, upregulating or inhibiting, respectively, virus production and gene expression.	110–113, 115–120
	HIV-1 inhibits STAT5 signaling pathways (e.g., IL-2, IL-7, and GM-CSF activated). HIV-1 Nef inhibits STAT5 expression in hematopoietic progenitors to inhibit multipotency.	107–111, 114, 121
WNV	WNV inhibits STAT5 activation in response to IFN-β/IL-4.	124
ZIKV	ZIKV inhibits JAK1/TYK2 and STAT5 activation in response to IFN-β/IL-4.	124

^aLightface and boldface indicate stimulatory and inhibitory effects, respectively, on STAT5.

The relationship between HIV-1 and STAT5 is complex, with reports of impaired and enhanced STAT5 responses (Table 4) (107–114). These discrepancies may arise in part from differences in viral strains and experimental approaches but are also likely to be related to the roles of STAT5 in controlling latency. In response to cytokines (e.g., IL-2 and IL-15), pY-STAT5 activates transcription from a STAT5-binding site within HIV-1 long terminal repeats (LTRs), inducing reactivation (Fig. 2C) (113, 115–119). Interestingly, a naturally occurring C-terminally truncated STAT5 isoform is present in HIV-1-infected peripheral blood mononuclear cells and binds the LTR but represses gene expression and virus reactivation, likely due to truncation of the transactivation domain (Fig. 1A) (112, 120). Further complicating the STAT5 story, secreted HIV-1 Nef protein deregulates the multipotency of uninfected early hematopoietic progenitors by downregulating STAT5 expression via the PPARγ pathway, contributing to hematopoietic deficiency and immunodeficiency in AIDS patients (121). Thus, STAT5 activity appears to be dynamically modulated by HIV-1 in infected and bystander cells to control cellular fate and support or reverse latency. The genome of human parvovirus B19 (B19V) also contains a pY-STAT5-binding element, which functions in replication initiation by recruiting the minichromosome maintenance complex (Fig. 2D) (122, 123).

Reports of STAT5 antagonism are limited (Table 4), but the flaviviruses West Nile virus (WNV) and ZIKV were recently shown to inhibit STAT5 phosphorylation in dendritic cells in response to type I IFNs and IL-4, but not granulocyte-macrophage colony-stimulating factor (GM-CSF) (124). Interestingly, these viruses appear to use distinct antagonistic mechanisms, while other flaviviruses, dengue virus and yellow fever virus, had no effect on STAT5 phosphorylation, indicating virus-specific roles (124).

STAT6

STAT6 is primarily implicated in signaling by the functionally related cytokines IL-4 and IL-13, which have cooperative and nonredundant roles in T helper 2 (Th2) differentiation, immunoglobulin class switching, macrophage activation, and major histocompatibility complex class II (MHC-II) expression and are key players in defense against extracellular parasites (125, 126). STAT6 is also activated by other cytokines (Table 1), including type I IFNs (126). A noncanonical role for STAT6 in innate immune responses has also been reported, involving stimulator of interferon genes (STING) (127), a sensor of cytosolic DNA and adaptor protein for signaling by certain sensors of viral RNA. Typically, STING recruits TANK-binding kinase 1 (TBK1) and IRF-3, leading to induction of type I IFNs, but STING was shown to also interact with and promote phosphorylation of STAT6 independently of cytokine and JAK signaling, via TBK1 and an unknown kinase (127). This causes upregulation of a specific set of STAT6 target genes different from those of the canonical JAK-STAT6 pathway, including certain chemokines. Consistent with an antiviral role, STAT6-deficient mice were more susceptible to infection by DNA and RNA viruses (127). Interestingly, earlier studies found that STAT6-deficient mice were less susceptible to disease caused by HSV-1 (128) or ectromelia virus (129). The differences may be related to the distinct disease models used and the complex outcomes of Th1/Th2 dysregulation (due to the lack of STAT6) in an in vivo setting, highlighting the multifaceted nature of STAT6 function during infection.

Persistent STAT6 activation is associated with several cancers (130–132), and similar to STAT3 and STAT5, STAT6 can be activated by viral proteins directly or via upstream pathways (e.g., upregulation of IL-13 by EBV Zta protein [133]), promoting transformation (Table 5). Since the EBV LMP1 promoter contains a STAT6-binding site, which is activated by IL-13 and IL-4 (Fig. 2A) (134), this indicates a proviral role for IL-13. Perhaps the best-characterized STAT6-virus interaction is with KSHV, where infection induces constitutive, albeit modest, phosphorylation via upregulation of IL-13 and downregulation of the PTP SHP1, promoting cell survival and proliferation (135, 136). However, recent studies have indicated that modulation of STAT6 through the KSHV infectious cycle is dynamic and complex, with differential regulation of STAT6 expression and activity important in the lytic and latent phases characteristic of herpesviruses.

TABLE 5.

Examples of viral regulators of STAT6^a

Virus	Effect on STAT6	Reference(s)
Herpesvirus saimiri	Herpesvirus saimiri Tip interacts with STAT6 and promotes STAT6 activation/gene expression, promoting cell transformation.	270, 271
HTLV-1	HTLV-1 Tax upregulates transcription from the IL-13 promoter, promoting IL-13/STAT6 signaling and cell survival/transformation.	272
EBV	EBV Zta upregulates transcription from the IL-13 promoter, promoting IL-13-induced cell proliferation. IL-13/IL-4-activated STAT6 binds and activates transcription from the LMP1 promoter in viral genome.	133, 134
	STAT6 expression is reduced during lytic EBV infection.	138
KSHV	KSHV induces basal STAT6 phosphorylation through upregulation of IL-13 and downregulation of SHP1, promoting cell proliferation.	135, 136
	KSHV LANA binds and induces truncation of STAT6, inhibiting IL-4/STAT6 signaling. Truncated STAT6 binds the RTA promoter in the viral genome, inhibiting RTA expression/virus reactivation. KSHV RTA binds STAT6 and induces STAT6 proteasomal/lysosomal degradation to promote virion production.	135, 137, 138

^aLightface and boldface indicate stimulatory and inhibitory effects, respectively, on STAT6.

It was originally reported that during latent infection the KSHV-encoded LANA protein inhibits STAT6 phosphorylation and transactivation activity in response to IL-4, thereby inhibiting IL-4-induced B cell activation and proliferation (135). However, a subsequent study indicated that LANA binds to STAT6 independently of tyrosine phosphorylation and induces accumulation in the nucleus, where STAT6 is cleaved to generate a “dominant-negative” protein with a truncated transactivation domain (137). The truncated STAT6 binds to a canonical STAT6-binding site in the promoter of KSHV replication and transcription activator (RTA), the key mediator of viral reactivation, preventing RTA transcription and maintaining latency (Fig. 2E) (137). Consistent with prolatency functions, STAT6 depletion induced RTA expression and virion production (135, 137, 138). Notably, IL-4/STAT6 signaling is also reported to induce RTA expression and reactivation of KSHV (139, 140), suggesting that full-length STAT6 may be able to activate transcription from the RTA promoter. Delineation of the precise biological relationship of these observations awaits further investigation.

During lytic replication of KSHV, RTA interacts with and ubiquitylates STAT6, inducing degradation (138), presumably to release the repressive activity of truncated STAT6 on RTA expression and reactivation. The effect of STAT6 degradation on cytokine signaling has not been examined, but it would be expected to be inhibitory and so contribute to both the latent-lytic switch and immune evasion, the latter being important during productive infection. Notably, the STAT6 degradation mechanism appears to be conserved among the human herpesviruses EBV, HCMV, and HSV-1 (138). For EBV, degradation of STAT6 during lytic infection is consistent with roles of STAT6 in inducing the prolatency factor LMP1 (see above).

KSHV encodes multiple STAT6-binding proteins, indicating the importance of STAT6 subversion to infection. Interestingly, STAT3 is also implicated in the KSHV latent-lytic switch, as it is activated during latency (141), with inhibition and depletion resulting in reactivation (43, 106). A number of KSHV proteins and mechanisms activate STAT3 (75, 141–145), while STAT3 repression for reactivation might involve KSHV-encoded miRNAs (106). RTA and LANA also interact with STAT3, although these interactions contrast with those for STAT6 (see above), as they promote STAT3 activity (138, 145, 146), highlighting how individual viral proteins can target different STATs with distinct outcomes. In addition to regulating STAT3 and STAT6, KSHV promotes and inhibits different STAT5 cytokine signaling pathways (see above) and blocks STAT1/2 signaling to antagonize type I IFN responses (147, 148). KSHV thus provides a clear example of how viruses can dynamically modulate STAT biology and nonredundant STAT pathways to induce conditions favoring infection and spread.

STAT HETERODIMERS

Many cytokines activate multiple STATs to induce an array of homo- and heterodimers (Table 1), presenting an additional level of complexity in viral targeting. For example, while STAT3 signals as a homodimer, several cytokines also induce STAT3 heterodimers with STAT1, STAT4, or STAT5 (Table 1) (4). The factors defining the composition of the cellular pool of activated STAT homodimers and heterodimers are poorly understood but likely depend on the stimulating cytokine(s) and receptor(s), the concentration and stoichiometry of different STATs, and the cell type. The role of heterodimers also remains controversial (4), including the function of STAT3 in IFN signaling (see above); in one study, STAT3 was proposed to effect inhibitory sequestration of STAT1 into STAT3-STAT1 heterodimers (25), while others reported positive roles in ISG expression (20–23).

Different STATs have differing affinities for promoter sites (149, 150), suggesting that heterodimers activate distinct gene subsets compared to the homodimeric counterparts. This is supported by reports that monocyte colony-stimulating factor (M-CSF)-activated STAT5-STAT3 heterodimers bind to a DNA element distinct from that bound by STAT5 homodimers (151) and that IL-35-activated STAT1-STAT4 heterodimers bind to promoters of Ebi3 and Il12a but not Irf1 (a classical STAT1 target) or Il18ra (a classical STAT4 target) (152). STAT heterodimers may also have distinct interactions with other transcription factors, coactivators, and corepressors. This is well understood for STAT1, homodimers of which bind to GAS sites, while STAT1-STAT2 heterodimers bind IRF9 and target ISREs (5). Thus, the various homo- and heterodimers formed by specific STATs are likely to have distinct biological significances, so that dimer-selective targeting by viruses would be expected to significantly impact transcriptional responses and might contribute to the apparent capacity of some STATs to be pro- and antiviral.

Despite this, analysis of viral targeting of specific homo- and heterodimers has remained somewhat limited. Electrophoretic mobility shift assays have indicated that rabies virus (RABV) P protein, which interacts with IFN-activated STAT1 and -2, blocks DNA binding of STAT1 homodimers and STAT1-STAT2 heterodimers (153). IAV NS1 protein impaired DNA binding of STAT1 and STAT3 homodimers and STAT3-STAT1 heterodimers following IFN-β activation, as expected, since IAV inhibits STAT activation (154).

Selective STAT targeting can also be inferred through analysis using STAT1-deficient cells. Such assays indicated that MUV V protein targets STAT1 and STAT3 independently to evade signaling by IFN and IL-6, so all STAT1- and STAT3-containing complexes are likely to be affected (57, 60). In contrast, recent data have indicated that antagonism of IL-6-activated STAT3 by RABV P protein is dependent on STAT1, so that P protein targets STAT3 only in the context of STAT3-STAT1 heterodimers (155). This appears to represent a mechanism to differentially regulate target genes of STAT3 homo- and heterodimers (155). A similar selectivity in viral stimulation of STATs was reported for HIV-1 Nef protein, which induced DNA binding of STAT1 homodimers and STAT3-STAT1 heterodimers, but not STAT3 homodimers, in monocyte-derived macrophages (156). A greater focus on resolving viral specificity for STAT complexes and consequences for the transcriptome should give valuable insights into viral modulation of the cell and the specific roles of distinct STAT dimers in cellular physiology, a poorly understood area in biology.

NONCANONICAL STAT FUNCTIONS

It is becoming increasingly clear that STATs have functions distinct from canonical JAK/STAT signaling (Fig. 3), so virus-STAT interactions are likely to have impacts beyond cytokine responses. It is generally accepted that non-tyrosine-phosphorylated “U-STATs” can dimerize, shuttle between the nucleus and cytoplasm, and bind DNA (157, 158) to activate specific subsets of the genes regulated by their pY-STAT counterparts (159–161) or distinct gene sets (162–165) or to effect gene repression (166–168). Importantly, STAT1 and STAT3 gene expression is induced by pY-STAT1 and pY-STAT3, so many cytokine responses are characterized by an initial transient pY-STAT-mediated gene expression profile followed by a “second wave” of genes activated by upregulated U-STATs (169).

FIG 3.

Noncanonical STAT functions. (A) U-STAT1 to -3, -5a/b, and -6 are reported to have intranuclear gene-regulatory function. (B) STAT1, -3, -5, and -6 localize to mitochondria and regulate metabolism, cancer cell growth and proliferation, the mitochondrial permeability transition pore, mitochondrial gene expression, and autophagy. (C and D) Cytoplasmic STAT3 inhibits PKR to repress autophagy induction (C) and stathmin to stabilize microtubules (D). (E) pY-STAT3 accumulates at focal adhesions in ovarian cancer cells, potentially contributing to invasiveness. (F) U-STAT5a/b localize to the ER and Golgi apparatus and promote structural integrity. (G) STAT6 is recruited to the ER by STING following viral nucleic acid detection and is phosphorylated by non-JAK kinases before translocation to the nucleus to activate gene expression. (H) Cytoplasmic STAT4 promotes type I IFN induction in response to RNA viruses by binding the E3 ligase CHIP to protect RIG-I from proteasomal degradation.

Outside the nucleus, STAT1, -3, -5, and -6 can localize to mitochondria to mediate STAT-specific functions (170–172), while STAT2 is implicated in mitochondrial fission (173). The best-characterized mitochondrial association is that of STAT3, which regulates the electron transport chain and the mitochondrial permeability transition pore (172). Cytoplasmic STAT3 can also inhibit autophagy and stabilize microtubules via interaction with protein kinase R (PKR) (174) and stathmin (175, 176), respectively. pY-STAT3 was additionally reported to localize to focal adhesions in cancer cells (177). Interestingly, U-STAT5 is found in the Golgi apparatus and endoplasmic reticulum (ER), with a role in structural integrity (178, 179). As discussed above, STAT6 (127) and STAT4 (93) have roles distinct from JAK/STAT signaling in innate antiviral responses.

This raises important questions as to how viral targeting of STATs affects noncanonical functions and whether these functions are pro- or antiviral. Since pY-STATs activate expression of their corresponding U-STATs, viruses that induce and enhance pY-STAT signaling are likely to upregulate U-STAT functions. The proviral role of STAT3 toward HCV has been partially attributed to microtubule stabilization (68), providing a possible reason for the promotion of STAT3 activity by HCV (Table 3). Moreover, viral activation of STAT3 is implicated in inhibition of autophagy by HIV-1 (180), EBV (74), and KSHV (181). Autophagy can be anti- or proviral, depending on the virus (182), so distinct requirements might contribute to the differing nature of STAT3 targeting by different viruses. Mitochondrial function is also commonly impacted by viruses (183). The extent to which this involves virus-STAT interactions is unclear, although phosphorylation of STAT3 S727, induced by several viruses (73, 75, 76), is associated with mitochondrial roles. Notably, a number of viruses induce S727 phosphorylation of STAT3 and/or STAT1 in the absence of tyrosine phosphorylation (75, 76, 184, 185). This noncanonical “monophosphorylation” is thought to promote aberrant inflammatory responses, contributing to pathogenesis (186). For example, S727-monophosphorylated STAT3 induced by KSHV kaposin B protein drives the expression of a specific subset of STAT3 target genes, including those encoding the inflammatory mediators IL-6 and CCL5 (75).

This diversity of STAT functions might underpin the array of strategies by which different viruses, or different proteins of the same virus, antagonize STATs. Many paramyxoviruses use V protein to target STAT1, -2, and/or -3 for degradation (56, 57), which would be expected to impact canonical and noncanonical functions with broad effects on cell biology. While many antagonists bind and inhibit STATs irrespective of cytokine stimulation, RABV and adenovirus effect mislocalization of STATs only in cytokine-stimulated cells (187–190). Notably, RABV P protein efficiently binds STAT1, -2, and -3 only following cytokine activation (187–189), presumably ensuring that P protein (which has key functions in replication) is diverted to STAT antagonism only as required. This might also permit important cellular functions of U-STATs, but not those of antiviral cytokines and pY-STATs. This diversity likely evolved due to distinct properties of viruses, including cell tropism and infectious-cycle duration. Clearly, the effects of viruses on broader noncanonical STAT functions is likely an important, but largely overlooked, aspect of infection.

THERAPEUTIC POTENTIAL OF VIRUS-STAT INTERFACES

A detailed understanding of the virus-STAT interface should provide opportunities for therapeutic or prophylactic approaches. Where STATs are proviral, pharmacological inhibition is a promising avenue, particularly given extensive research on inhibitors of STATs and STAT pathways (primarily STAT3 and STAT5) for diverse malignancies (191) that could be repurposed. Importantly, in vitro, ex vivo, and animal studies have indicated the potential of such compounds: inhibition of specific STATs or upstream components (e.g., JAKs) can inhibit replication (e.g., B19V [122, 123], HCV [67, 68], HPV [103], HCMV [71], and varicella-zoster virus [192]) and virus-induced cell proliferation and transformation (e.g., HCMV [193], HBV [51], and HTLV-1 [194]). The FDA-approved JAK inhibitors tofacitinib and ruxolitinib block HIV-1 replication and reactivation by preventing STAT5 phosphorylation and LTR binding (113, 195). While this disrupts virion production and dissemination, it cannot eradicate latent reservoirs. However, benzotriazoles were identified as promising inducers of reactivation, which could potentially be used in a “shock and kill” strategy (117). Notably, benzotriazoles block STAT5 sumoylation, a PTM that negatively regulates STAT5 activity, highlighting PTMs other than tyrosine phosphorylation as potential targets. Among these, serine phosphorylation of STATs may be significant based on reports of viral induction (73, 75, 76, 184, 185) and potential roles in inflammation and pathogenesis (186).

Inhibition of STAT3 induces reactivation of latent herpesviruses (42–45), an important finding given the challenges latent reservoirs present for therapy. The utility of this approach was recently indicated by the finding that the combination of the STAT3 inhibitor Stattic with an antiviral that blocks KSHV replication potently inhibited virion production (106). Since the latent and lytic switches of EBV and HSV-1 can also be induced by STAT3 inhibitors (42, 44), this represents an attractive potential treatment strategy for herpesviruses more generally (106). Modulating STAT function is thus a promising avenue for management of diverse viruses, although its effectiveness in the clinic remains to be determined.

Given the critical roles of IFN antagonists in shutting down antiviral responses and the consequent significance to pathogenesis, they present attractive targets for vaccine and antiviral drug development. Screening approaches have identified IFN antagonist inhibitors (196–199), and the development of viral reverse genetics systems enables site-directed mutagenesis for the design of potential “live” attenuated vaccines (3, 6). A number of important viruses are attenuated by deletion of STAT1/2 antagonists (e.g., respiratory syncytial virus NS2 [200] and MEV V and C [201] proteins). Influenza A and B viruses are attenuated by deletion or truncation of the gene encoding NS1, which blocks STAT1 to -3 signaling (154), and potential application for vaccines has been explored in animal models and clinical trials (202–206). Notably, these antagonists are multifunctional, so STAT signaling would not be the only process impacted by deletion.

Many IFN antagonists, however, have additional critical functions in replication, so deletion or truncation can render a virus nonviable. Attenuation thus requires mutations that can selectively disrupt antagonistic function. “Forward genetic” approaches comparing virus strains and species of differing virulences have enabled the identification of mutations and substitutions impacting STAT1/2 antagonism that correlate with pathogenesis (e.g., Sindbis virus [207], WNV [208], RABV [209], and Ebola virus [210, 211]). Reverse genetics analysis has directly supported STAT antagonism as a specific pathogenicity factor. Mutations in the V or P gene of MEV or MUV that inhibit STAT1 or STAT3 antagonism attenuated virus in rhesus monkeys (212) and reduced neurovirulence in rats (59), respectively. Different mutations impacting STAT1 binding by the RABV P protein rendered a fixed pathogenic strain nonlethal and significantly attenuated a pathogenic street strain, although the latter remained lethal, consistent with important roles of other immune evasion mechanisms (213, 214). Similarly, a single mutation in the NIV V or P gene that disrupted STAT1 binding did not significantly affect lethality in ferrets, although it altered the disease course (215). Thus, targeting of virus-STAT interactions has potential to provide methods for attenuation, but generation of live vaccines clearly requires a combination of several attenuating mutations, potentially including mutations impacting other immune evasion mechanisms, to achieve a sufficient attenuation and safety profile.

CONCLUDING REMARKS

The interface of viruses with STATs is clearly highly diverse and dynamic, reflecting the diversity and evolutionary complexity of viruses and the array of functions associated with STATs. Furthermore, it appears that idiosyncrasies of the virus and host cell, including the duration of the infectious cycle, whether the virus can become latent, cellular expression of STAT family members, and exposure to specific cytokines, are critical determinants of the significance of particular STATs, including their propensities for anti- or proviral roles. Importantly, for many viruses, these requirements appear to change throughout infection, necessitating the evolution of strategies to both induce and suppress the functions of a specific STAT.

As our understanding of the scope of STAT functions expands, so do the implications for the viral interface. In particular, increasing evidence of targeting of STATs other than STAT1/2 suggests that much of the virus-STAT interface has been overlooked in terms of targeting of both individual STATs and specific complexes, which might enable exquisite regulation of the transcriptome. Viral modulation of noncanonical STAT functions also remains poorly defined. Delineation of these elements is significant for the potential development of new antiviral and vaccine approaches.

Finally, as in many areas of virological research, the virus-STAT interface has implications beyond infection. Through the evolution of specific mechanisms to modulate cell biology, viruses have provided invaluable tools to dissect many complex cellular processes. Elucidation of the molecular mechanisms underlying viral modulation of specific STAT pathways might have far-reaching implications for our understanding of cellular signaling, transcriptional regulation, and immunity, with significance for other pathologies, including cancer.

Biographies

Angela R. Harrison obtained her Bachelor of Science degree from Monash University (Australia) as a part of the competitive Science Scholar Program, focusing on Microbiology and Biochemistry. She then obtained First Class Honors from the University of Melbourne (Australia) in the laboratory of Dr. Gregory Moseley, where she was awarded the AB-SCIEX Honours Prize, before moving with Dr. Moseley to Monash University to undertake her Ph.D. Ms. Harrison’s research focuses on the immune evasion strategies of highly pathogenic lyssaviruses and Ebola virus, including targeting of STAT3 complexes to suppress responses to interleukin-6 family cytokines.

Gregory W. Moseley did his undergraduate studies in Biochemistry at the University of York (United Kingdom) before undertaking research toward a Ph.D. at The University of Sheffield (United Kingdom) and Walter and Eliza Hall Institute (Australia) on the roles of tetraspanin proteins in immunity. Under the auspices of a Royal Society postdoctoral fellowship, he pursued research in immunology at the Austin Research Institute (Australia). He subsequently moved to Monash University (Australia) to pursue research on protein trafficking, and established a laboratory investigating the molecular mechanisms of viral immune evasion and pathogenesis. He also undertook visiting positions in Gifu University (Japan) and CNRS (France). In 2013, he was awarded the Grimwade Fellowship at the University of Melbourne and in 2017 took a tenured position in the Department of Microbiology, Monash University, where his laboratory continues to probe the mechanisms underlying viral immune evasion, including targeting of STAT proteins, the topic of this review.