Restriction Factors against Human Cytomegalovirus
Santo Landolfo1*, Marco De Andrea1,2, Marisa Gariglio2
1Viral Pathogenesis Unit, Department of Public Health and Pediatric Sciences, Medical School, University of Turin, Italy.
2Virology Unit, Department of Translational Medicine, Medical School of Novara, Italy
*Author for correspondence: Viral Pathogenesis Unit,Department of Public Health and Pediatric Sciences, Medical School, University of Turin. Via Santena, 9 – 10126 Turin, Italy - Tel.: +39 011 670 5636, Fax: +30 011 670 5648, email: santo.landolfo@unito.it
Keywords: Human Cytomegalovirus (HCMV), restriction factor (RF), Nuclear Domain 10 (ND10), Interferon, IFI16, Viperin.
Summary
Cellular proteins called “restriction factors” (RFs) form an important component of the innate immune response to viral replication. However, over time viruses have learned how to antagonize RFs through mechanisms that are specific for each virus. Here, we summarize the general hallmarks of RFs before going on to discuss the specific strategies recruited by some key RFs that strive to hold Human Cytomegalovirus (HCMV) infection back, as well as the counter-restriction mechanisms employed by the virus to overcome this innate defense. Such RFs include the cellular proteins PML, hDaxx, and Sp100 (constituents of Nuclear Domain 10: ND10) and IFI16, a nuclear protein and member of the PYHIN protein family. Viral regulatory proteins, such as IE1 or pp71, try to oppose the ND10-induced blockade of virus replication by either modifying or disrupting this RF. IFI16, on the other hand, inhibits virus DNA synthesis by down-regulating the transcription of viral gene UL54; the intruding virus attempts to antagonize IFI16 by mislocalizing it from the nucleus to the cytoplasm via the action of viral protein UL97. Finally, we consider how Viperin, a RF initially thought to inhibit HCMV maturation late during infection, has actually been demonstrated to enhance virus maturation by increasing lipid metabolism and enhancing virus envelopment. All in all, detailed knowledge of these HCMV restriction and counter-restriction mechanisms will provide new insights into how we might control HCMV infection and, in turn, contribute to the development of novel therapeutic interventions.
Introduction
The mammalian immune system has developed an arsenal of defense mechanisms, including innate and adaptive immune responses, primarily responsible for protecting cells against viral pathogens [1]. Classical innate immunity against viruses is mediated by specialized cells, including natural killer cells, dendritic cells, and macrophages. However, recent work has also discovered the existence of cellular-based defense mechanisms, now known as intrinsic immunity, giving rise to a third branch of the traditionally bipartite immune system [2]. The cellular proteins directing this form of antiviral activity are often termed “restriction factors” (RFs), as they inhibit viral replication [3]. However, viruses have themselves evolved mechanisms to evade and defend themselves against this form of host intrinsic immunity [4,5]. Indeed, the defense and counter-defense measures generating this antagonistic conflict have molded both viral and host cell functions and genomes. The term “restriction factor” was historically adopted by laboratories studying retroviruses following the observation that the mouse Friend virus susceptibility factor-1 (Fv1 locus) conferred resistance to murine retroviruses [6,7]. In the mouse genome, there are at least two Fv1 alleles (Fv1n, Fv1b) conferring resistance to B-tropic murine leukemia virus (B-MLV) and N-B-tropic MLV (N-MLV) infection. The B-MLV strains efficiently infect Fv1b/b homozygous BALB/c mice, but not the Fv1n/n homozygous NIH/Swiss mice, whereas the N-MLV strains exhibit the opposite tropism [6]. Fv1 blocks the nuclear import of reverse transcribed retroviral pre-integration complex [8], but the precise mechanism is still unknown. Retroviruses have come to represent a model system that has been instrumental in expanding our understanding of how viruses and hosts interact. Indeed, the concept of “intrinsic immunity” arose from the discovery that prototype human antiretroviral restriction factors, such as APOBEC3G, TRIM5, and Tetherin, are constitutively expressed in cell types targeted by primate lentiviruses, where target cells are resistant to infection in the apparent absence of any signaling event [9–14]. Although it is now apparent that the expression of most restriction factors can be increased by interferon (IFN),
IFN-induction is not required for constitutive antiretroviral activity in target cells. Thus, there is a clear and critical biological distinction between intrinsic (pre-existing) immunity and IFN-dependent innate immunity.
Innate Immunity
Typically, in the first step of the innate immune response, viral nucleic acids and proteins are recognized as pathogen-associated molecular patterns (PAMPs), hallmarks of infection usually absent from healthy host cells. Endosomal Toll-like receptors (TLR3, TLR7/8 and TLR9) and cytosolic pattern recognition receptors (PRRs) (reviewed by [15,16]) can detect viral DNA and RNA species, including double-stranded (ds) RNA, single-stranded (ss) RNA, and DNA containing CpG motifs [17–19]. A variety of cell types including macrophages, dendritic cells and keratinocytes can detect PAMPs via TLRs located in the endosomes. However, it has recently emerged that many cells can also detect nucleic acids in their own cytosol during viral infection, and this occurs in a TLR-independent manner. The cytosolic RNA receptors MDA5 (Melanoma Differentiation-Associated factor 5) and RIG-I (Retinoic acid-Inducible Gene 1) detect dsRNA and ssRNA with a 5’-triphosphate group in the cytoplasm of cells infected with RNA viruses (reviewed by [20]).
Pathogen DNA constitutes one of the most important PAMPs signaling infection by intracellular pathogens, such as bacteria and viruses [21–23]. The predominant sensor of cytosolic DNA is the IFN-inducible PYHIN family protein AIM2 (Absent in Melanoma 2), which binds DNA via its HIN domain and then activates multiple signaling cascades leading to inflammasome complex formation and IFN-b production [24–28]. While AIM2 acts as a cytoplasmic sensor, another member of the PYHIN family, designated IFI16, senses pathogenic DNA both in the cytoplasm and the nucleus [29–34]. The detection of exogenous DNA by IFI16 then initiates two distinct innate immunity signaling cascades: the first involves the activation of transcription factors Interferon Regulatory Factor 3 (IRF3) and nuclear factor kappa B (NF-B), which result in the transcription of IFN-, chemokines, and
pro-inflammatory cytokines [32]. The second signaling pathway results in the formation of an inflammasome complex, which activates caspase-1, a protease that processes pro-interleukin (IL)-1 and pro-IL-18 to generate active cytokines ready for secretion [35,36]. Thus, viral infections are detected by cytoplasmic, membrane-bound or nuclear PRRs, which trigger an response that induces the expression of IFN-stimulated genes, many of which are RFs that specifically inhibit viral growth within infected cells.
General Restriction Factor Characteristics
Restriction Factors are germline-encoded factors that mediate a cell-intrinsic immune response. They can also be classified as PRRs because they directly recognize and bind to viral components [3,37]. However, unlike TLRs and RLRs, which activate signaling cascades that inhibit virus infection indirectly, RFs inhibit viral replication by directly interfering with the activity of essential viral genes, often before the activation of the IFN response. Thus, RFs are characterized by properties that differentiate them from pathogen sensors. Briefly, RFs: i) autonomously exhibit antiviral activity in culture-based assays and inhibit specific processes in viral replication; ii) are constitutively expressed in various cell types, but can be induced by IFNs; iii) are often antagonized by viral proteins; and iv) are subject to positive genetic selection driven by host-pathogen coevolution. Indeed, the notion of “intrinsic immunity” emerges from the early observation that prototype human antiretroviral factors, such as APOBEC3G and TRIM5, were found constitutively expressed in cell types targeted by primate lentiviruses in the complete absence of any signaling event [2,38]. Thus, the concept of intrinsic immunity served as a basis to explain why defined cell lines are “restrictive” or “permissive”, depending on whether wild-type or mutant viruses could efficiently replicate therein. Although intrinsic immune mechanisms were discovered as being active against retroviruses [3,39,40], increasing evidence suggests that such mechanisms also counteract several other viruses, including Herpesviruses [41–43]. In present review, we therefore concentrate on the most recent discoveries regarding human cytomegalovirus
(HCMV) and describe how the actions of different restriction factors affect different steps of its replication. Interestingly, evidence also implicates HCMV as having evolved mechanisms to counteract these restriction factors, which ultimately leads to the successfully replication of this virus in target cells.
Nuclear Domain 10 (ND10)
Nuclear domain 10 (ND10; also known as PML nuclear bodies or PODS) are discrete bodies of accumulated proteins located within the nuclear matrix, an ill-defined structure within the nucleus proposed to anchor and regulate various nuclear functions [44,45]. PML protein (a member of the TRIM/RBCC family of proteins), hDaxx, and Sp100 are the key constituents of ND10 and they organize the nuclear matrix by recruiting proteins characterized by their ability to be SUMOylated [46,47]. The recruited proteins include an ubiquitin-like protein named SUMO, and the conjugation of PML to SUMO plays a critical role in the recruitment of other partners [48–50]. The ND10 body is a sphere with a diameter ranging between 0.1-1 m, and which may present a granular center. These proteinaceous bodies are typically found in clusters of 5 to 15 and do not contain RNA or DNA [51]. PML protein is located in the outer shell of the structure, with its associated partners residing inside. ND10 are distributed within the interchromosomal space, frequently adjacent to other bodies. Functionally, ND10 have been implicated in the regulation of diverse cellular key processes, like oncogenesis [52–54], DNA damage repair [55], apoptosis [56–58], senescence [59–61], and the regulation of gene expression [44,49]. Interestingly, ND10 undergo profound modification during virus infection [55,62–65]. They appear to accumulate viral genome at their periphery or within their central core during infection of quiescent cells. Together with the knowledge that IFNs increase the gene transcription of PML, hDaxx, and Sp100 [66,67], these findings point to a role of ND10 in the regulation of the antiviral response.
Initially regarded as the optimal cellular site for the initiation of HCMV IE gene expression, whose transcripts are juxtaposed to these domains, it soon became apparent that the virus targets ND10 early during infection in order to destroy them [68–72]. This activity, executed by the viral regulatory protein IE1, correlated with efficient lytic replication cycle. Important advances in the comprehension of the biological role of ND10 in the prevention of viral replication came from the finding that depletion of PML from ND10 bodies by specific small interfering RNA (siRNA) rendered human primary foreskin fibroblasts (HFF) more susceptible to HCMV infection [73]. Together, these observations support the notion that ND10 bodies regulate an intrinsic immune response of the cell that exerts its antiviral activity by down-regulating viral IE gene expression. Interestingly, HCMV infection of PML-null HFF induced de novo formation of two other protein constituents of ND10 bodies, namely hDaxx and Sp100 [73]; hence, it emerged the concept that HCMV triggers an active recruitment of ND10 components to the site of viral nucleoprotein complex. Moreover, it has been suggested that other ND10 associated proteins, like hDaxx and Sp100, could indeed form part of the intrinsic antiviral response instituted by ND10 bodies [74,75].
The scenario that emerges from studies performed by different group shows that the three major ND10 proteins – PML, hDaxx, and Sp100 – repress viral replication by silencing viral IE gene expression [72,74–77]. Furthermore, in infection experiments exploiting all possible double knock-down combinations of the ND10 constituent proteins, the initiation of HCMV gene expression is enhanced compared to that in the respective single-knock down cells [75]. These finding clearly argue for an independent role of these factors in the suppression of HCMV replication. Furthermore, some authors predict that epigenetic mechanisms are involved, capable of preventing viral genome transcription and lytic replication [78,79]. During early infection, viral DNA has been found to exist in a repressive chromatin state, modulated by posttranslational histone modification [80]. The ND10 protein responsible for inducing a transcriptionally inactive chromatin state of the
immediate-early enhancer/promoter (MIEP) has been identified as being hDaxx [81,82]. The state is induced via recruitment of the chromatin remodeling protein ATRX (alpha thalassemia/mental retardation syndrome X-linked) or of chromatin modifying enzymes, like histone deacetylases (HDACs), to the viral DNA [79,83]. Similarly, PML and Sp100 have also been demonstrated to interact with chromatin modifying enzymes, suggesting the involvement of epigenetic mechanisms in the repression of viral IE gene expression [71,84].
Despite the restriction activity orchestrated by the ND10 constituent proteins, the observation that HCMV is still able to replicate successfully indicates that the virus has co-evolved to counteract such activity. Soon after virus entry, the viral tegument protein and transactivator pp71 translocates and interacts with ND10 constituents [85]. The viral pp71 binds to hDaxx protein, which is responsible for silencing the MIEP and down-regulating IE gene expression [86]. Following pp71 binding, hDaxx undergoes proteasome degradation and relieves MIEP repression. However, recent studies by different groups have demonstrated that the scenario is more complex. Degradation of hDaxx is preceded by the release of the chromatin-remodeling protein ATRX from ND10, which is stimulated by pp71. As a consequence, the displacement of ATRX alleviates the repression of viral IE gene expression [83].
While pp71 appears to be responsible for counteracting both hDaxx- and ATRX-mediated gene silencing, the IE1 protein appears to abolish the repressive effects of PML. The IE1 protein synergizes with IE2 to promote the stimulation of several viral early and host gene promoters [87–90]. It has since been demonstrated that IE1, but not IE2, is able to stimulate the dispersal of the ND10 bodies with the displacement of their constituents proteins, such as PML and Sp100. IE1-mediated disruption of PML does not proceed via proteasomal degradation, but rather via de-SUMOylation that then leads to the inhibition of PML oligomerization [91].
In conclusion, it appears that the frontline defense against HCMV replication occurring soon after infection is accomplished by ND10 proteins. Moreover, it is now
well established that viral proteins, including pp71 and IE1 (FIGURE 1), are
responsible for the viral countermeasures put into effect in order to overwhelm these host restriction factors. Present research efforts are being directed at gaining a more detailed comprehension of the molecular mechanisms underlying the virus-host interactions mediated by ND10.
The PYHIN-200 family IFI16 protein
The IFN-inducible PYHIN-200 protein family includes the structurally related human AIM2, IFI16, IFIX, and MNDA [92]; murine homologues include, for example, p202, p203, and p204. All the proteins in the family share a conserved domain of 200-amino acid residues at the C-terminus, present in single or tandem copies. Three IFI16 protein isoforms exist, derived from alternative splicing [93]; all of which contain two 200-amino acid domains, A and B, separated by a spacer region of variable length. Most proteins of this family also contain a homotypic protein-protein interaction PYRIN domain (PYD) in the N-terminus [94]. The predominant B isoform can be detected in cells of different histological type, such as immune cells, endothelial cells, and epithelial cells [95,96]. The N-terminus of IFI16 protein contains a bi-partite nuclear localization signal (NLS). Accordingly, the subcellular localization of IFI16 is normally nuclear in resting cells, including: fibroblasts [29], endothelial cells, and keratinocytes (reviewed in [95,97]). Notably, within the nuclear compartment, IFI16 protein is also detected in the nucleolus [98]. Upon infection of macrophages or fibroblasts by Herpesvirus [34,99], or the exposure of keratinocytes to UV-B light, IFI16 is redistributed from the nucleus to the cytoplasm [100]. This redistribution of IFI16 protein was associated to inflammasome assembly in the case of Herpesvirus infection, and apoptosis in the case of UV-B exposure. Protein-protein interactions have been recognized as influencing the subcellular localization of proteins, and IFI16 protein can form homo- or heterodimers with several other proteins, including: p53, Rb, BRCA1, ASC, and STING [30,31,101–104]. However, the molecular mechanisms that regulate IFI16 redistribution between the nuclear and
the cytoplasmic compartment remain unknown. Finally, IFI16 has been shown to bind to DNA both in vitro and in vivo [30,105–107]. Consistent with this DNA binding ability, IFI16 has also been recognized to act as a viral DNA sensor in the cytoplasm and to play an important role in tuning the innate immune response by enhancing IFN-production [34,97]. It therefore seems conceivable that IFI16 redistribution within the cell depends, not only on the type of protein interactions occurring, but also the binding of IFI16 protein to pathogenic DNA.
Restriction of HCMV replication by IFI16 protein and virus evasion
Two members of the PYHIN family, namely AIM2 and IFI16, have been shown to function as PRRs of virus-derived intracellular DNA [28,31,35,108,109]. In particular, IFI16 has been demonstrated to interact with the adaptor molecule ASC and procaspase-1 to form a functional inflammasome during Kaposi Sarcoma Associated Herpesvirus (KSVH) infection [31]. Moreover, reducing the expression of IFI16, or its mouse ortholog p204, by means of RNA-mediated interference inhibited gene induction and the activation of transcription factors IRF3 and NF-κB normally seen after DNA transfection and herpes simplex virus type 1 (HSV-1) infection [32,110,111]. In addition its role as a PRR, many different functions had been ascribed to IFI16 protein, with the exception of any form of antiviral activity (reviewed in [92]). This view of IFI16 has changed over recent years thanks to the findings generated from two different experimental approaches. The first involved the silencing of IFI16 using specific siRNA or its inactivation by introducing a lentivirus expressing a dominant negative mutant form [109]. In both cases, the lack of functional IFI16 protein in human embryo lung fibroblasts (HELF) significantly enhanced herpesvirus replication, including that of HCMV. Consistent with these results, when HELF overexpressing IFI16 were infected with HCMV, a 2.5 log decrease in viral production was observed. To investigate the molecular basis of the antiviral activity of IFI16, the effects of IFI16 overexpression on the different phases of the HCMV replication cycle were examined. Transfection experiments with the
luciferase reporter gene driven by deleted or site-specific mutated forms of the HCMV polymerase (UL54) or UL44 promoters demonstrated that the inverted repeat element 1 (IR-1) is the target DNA motif of the IFI16 suppression. Suppression of the UL54 promoter was mediated by the IFI16-induced blocking of Sp1-like factors, as shown by electrophoretic mobility shift assays and chromatin immunoprecipitation. Accordingly, deletion of the Sp1 responsive element from the promoter of the UL44 protein, associated with UL54 in HCMV DNA synthesis, also relieved IFI16 suppression. Together, these results demonstrate that in addition to the previously recognized activity of IFI16 as DNA sensor, it also acts as restriction factor of herpesvirus replication [109] (FIGURE 2).
The fact that HCMV is still able to accomplish its replication cycle despite IFI16 restriction activity suggests that the virus has evolved evasion strategies to antagonize IFI16 activity. Insights into a possible HCMV evasion strategy have come from experiments using HCMV-infected fibroblasts (unpublished results). Early on during infection, IFI16 binds to virus DNA, however, at a later time point during viral DNA synthesis, IFI16 is mislocalized from the nucleus to the cytoplasm. The molecular mechanisms underlying this virus-induced nuclear egression of IFI16 require the binding of viral protein kinase UL97 to IFI16 (FIGURE 2). Upon binding, IFI16
undergoes phosphorylation, which in turn promotes its nucleo-cytoplasmic relocalization. The ESCRT (Endosomal Sorting Complex Required for Transport) machinery regulates thereafter the translocation of IFI16 into the virus assembly complex (AC). Finally, during the virus maturation step, IFI16 becomes incorporated into the new virions budding from the cells. Altogether, these results demonstrate that the strategy HCMV has evolved to evade IFI16 restriction activity consists of the nuclear egression of the protein followed by its incorporation into newly formed virions. It is likely that this is the event that leads to the inactivation of IFI16 antiviral activity.
Normal expression levels of the cellular protein Viperin are low. Its expression, however, is strongly induced by type I IFN, various viruses, lipopolysaccharide (LPS), and synthetic double-stranded RNA (poly I:C) [21,112,113]. It was initially demonstrated that infection of fibroblasts with HCMV triggered the expression of a subset of type I IFN-inducible genes. Two cDNA fragments, termed cig5 and cig33 (cytomegalovirus inducible gene 5 and 33, respectively) spanned the 5’-end and the 3’-end of the viperin mRNA, respectively [114]. Chin and Cresswell showed that these fragments contained the sequence of a HCMV-inducible mRNA and named the encoded protein “viperin” (standing for Virus Inhibitory Protein, Endoplasmic Reticulum-Associated, Interferon Inducible) [112]. In addition to HCMV, many viruses induce viperin expression including vesicular stomatitis virus and pseudorabies virus [115], Japanese encephalitis virus [116], sendai virus [113], West Nile virus [117], Chikungunya virus [118,119], hepatitis C virus [120], yellow fever virus [121], and human rhinovirus [122]. The viral induction of viperin may occur in a direct IFN-independent manner, or indirectly through the induction of IFN.
Several lines of evidence point to an antiviral function of viperin. For instance, viperin displays antiviral activity against influenza A virus by inhibiting virus release from infected cells. Through binding to and inhibiting farnesyl diphosphate synthase (FPPS; an enzyme essential for the biosynthesis of isoprenoid-derived lipids), viperin inhibits the release of influenza A virus from the plasma membrane by altering lipid raft organization and, in turn, budding [123]. In hepatic cells infected with hepatitis C virus, on the other hand, viperin acts by blocking the formation of the HCV RNA replication complex on the lipid raft – a process that requires the binding of host protein hVAP-33 to viral proteins NS5A and NS5B. By binding to hVAP-33, viperin disrupts the interaction with NS5A and NS5B, and thereby inhibits HCV replication complex formation and down-regulates virus replication [124].
However, while it was first thought that viperin acted as a restriction factor against HCMV infection, more recent evidence has brought to light a different scenario where it seems that HCMV actually exploits viperin to enhance its
expression. Stable expression of the protein before HCMV infection reduced the redistribution of viperin from the endoplasmic reticulum to the Golgi apparatus, thus preventing its vacuolar localization and inhibiting productive HCMV infection. Now it has been demonstrated that HCMV triggers an increase in lipogenesis in infected cells via a viperin-dependent pathway for its proper envelopment, mainly consisting of glycolipids [125]. The increase in lipogenesis follows the redistribution of viperin to mitochondria, where the protein interacts with and blocks the function of the mitochondrial trifunctional protein (TFP), the enzyme that mediates fatty acid- -peroxidation. This leads to a decrease of intracellular ATP, which in turn activates AMP-activated protein kinase (AMPK) and, consequently, the expression of the glucose transporter GLUT4; this is accompanied by an increase of glucose import and nuclear translocation of the glucose-regulated transcription factor ChREBP. As a consequence, the increase in the expression of enzymes involved in lipogenesis leads to an increased lipid synthesis and enhanced viral envelopment. Altogether, these findings demonstrate that HCMV maturation relies on its ability to exploit viperin activity in order to up-regulate lipid metabolism, needed for its proper glycolipid envelopment (FIGURE 3).
Nevertheless, since viperin also exhibits antiviral activity, it is in the interests of the virus to silence the protein. To prevent viperin antiviral activity, different viruses have adopted different strategies. For instance, the Chikungunya virus, which induces viperin expression via IRF3-mediated pathway, triggers a widespread cellular translation block, which down-regulates the synthesis of IFN-inducible genes including viperin [118]. Japanese encephalitis virus, on the other hand, although stimulating viperin expression, drives the protein to degradation by proteasomes [116].
Future perspectives
Significant progress has now been made into unraveling mechanisms RFs relying on to limit replication of HCMV. However, there is still significant scope for
future discovery and exploitation of RFs to cope HCMV infections. The evidence reviewed in this chapter supports the view that the innate antiviral immunity respond robustly following primary HCMV infection. This response is very likely protective in healthy immunocompetent individuals resulting in asymptomatic infections. However, despite this HCMV is able to establish latency and the virus is never eliminated from the infected individuals. A complex interplay between the innate antiviral and the adaptive immunity must exist in order to antagonize the HCMV-mediated immune evasion strategies that allow viral reactivation, extensive viral dissemination accompanied by clinical disease. A major challenge, therefore, will be to unveil the molecular mechanisms exploited by RFs to activate the adaptive immune response, that leads to the control of HCMV replication. A second major challenge will be the therapeutic exploitation of RFs biology that up to now has not received widespread attention. Indeed, the pharmacologic manipulation of RFs, aimed at blocking interactions between a viral antagonist and a host restriction factor, would appear as an attractive approach for the development of novel antivirals. However, consistent with their critical role in innate antiviral immunity, RFs such as IFI16 have been implicated in the pathogenesis of autoimmune diseases [126]. Therefore, it can be envisaged that such uncontrolled manipulation could possibly unbalance the immune response, favoring the onset of an autoimmune process.
Executive summary
Restriction factors (RFs) form an important component of the innate immune response to viral replication.
RFs so far described include: i) the cellular proteins PML, hDaxx, and Sp100, constituents of Nuclear Domain 10 (ND10); ii) IFI16, a nuclear protein and member of the PYHIN protein family; iii) Viperin (Virus Inhibitory Protein, Endoplasmic Reticulum-Associated, Interferon Inducible)
Human Cytomegalovirus (HCMV) and other viruses have developed specific strategies in order to overcome this innate defense system
The recently discovered property of IFI16 as RF for HCMV lies in its ability to inhibit virus DNA synthesis by down-regulating the transcription of viral gene UL54. The virus attempts to antagonize IFI16 by mislocalizing it from the nucleus to the cytoplasm via the action of viral protein UL97
Detailed information of these HCMV restriction and counter-restriction mechanisms will provide new insights into how we might contribute to the development of novel therapeutic interventions
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Legends to Figures
Figure 1. Restriction of HCMV replication by ND10 and virus evasion. Schematic representation of the mechanisms exploited by HCMV to overwhelm the biological role of ND10 proteins as restriction factors in the prevention of viral replication.
Figure 2. Restriction of HCMV replication by IFI16 protein and virus evasion. Nuclear IFI16 protein inhibits HCMV replication by blocking the activity of Sp1-like transcription factors on viral UL54 promoter. Conversely, HCMV mislocalizes IFI16 into the cytoplasm through its phosphorylation by the viral protein kinase UL97. Figure 3. HCMV exploits viperin to enhance its expression. For its proper envelopment, HCMV triggers an increase in lipogenesis in infected cells via a viperin-dependent pathway, involving cellular enzymes committed to lipid synthesis. In particular, Viperin interaction with the viral protein vMIA (viral mitochondrial inhibitor of apoptosis) results in Viperin relocalization from the endoplasmic reticulum to the mitochondria, and consequent reduced cellular ATP generation, which resulted in actin cytoskeleton disruption.
