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Kalamvoki, M. HSV-1 Non-Essential Proteins. Encyclopedia. Available online: https://encyclopedia.pub/entry/6237 (accessed on 29 November 2024).
Kalamvoki M. HSV-1 Non-Essential Proteins. Encyclopedia. Available at: https://encyclopedia.pub/entry/6237. Accessed November 29, 2024.
Kalamvoki, Maria. "HSV-1 Non-Essential Proteins" Encyclopedia, https://encyclopedia.pub/entry/6237 (accessed November 29, 2024).
Kalamvoki, M. (2021, January 10). HSV-1 Non-Essential Proteins. In Encyclopedia. https://encyclopedia.pub/entry/6237
Kalamvoki, Maria. "HSV-1 Non-Essential Proteins." Encyclopedia. Web. 10 January, 2021.
HSV-1 Non-Essential Proteins
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This entry is adapted from the peer-reviewed paper 10.3390/v13010017

Approximately half of the proteins encoded by the herpes simplex virus 1 (HSV-1) genome have been classified as non-essential. These proteins have essential roles in vivo in counteracting antiviral responses, facilitating the spread of the virus from the sites of initial infection to the peripheral nervous system, where it establishes lifelong reservoirs, virus pathogenesis, and other regulatory roles during infection.

HSV-1 non-essential proteins HSV-1 egress

1. Introduction

The large family of DNA viruses, Herpesviridae, have co-evolved with mammals for millions of years [1][2]. The family Herpesviridae is further divided into three subfamilies, Alphaherpesvirinae, Betaherpesvirinae, and Gammaherpesvirinae. Herpes simplex virus type 1 (HSV-1), a member of Alphaherpesvirinae, is one of the most well-studied representatives of this family of viruses and will be the focus of this review.

HSV-1 is an enveloped dsDNA virus, which has a genome size of about 152 kb and virion size of about 150–300 nm in diameter [3]. The virion contains the envelope decorated with viral glycoproteins and a proteinaceous layer known as the tegument, which surrounds the capsid of the virus containing the genome. HSV-1 is an important human pathogen, with approximately 80% of the human population infected [3]. Symptoms of HSV-1 infection vary, from lesions in the oral-facial region (“cold sores”), to herpes keratitis, the leading cause of infectious blindness, to herpes encephalitis, which can be fatal. When HSV-1 encounters a host, it will first infect the mucosal epithelial cells in the oral-facial region (although HSV-1 also causes genital infections). It is in these cells that the virus undergoes lytic replication. The virus will then infect innervating sensory neurons, travel anterograde to the trigeminal ganglia (TG), and establish latency, where it will remain for the life of the infected individual. When HSV-1 undergoes latency there are very few genes expressed, including an 8.3-kb region known as the latency-associated transcript (LAT), which is a long non-coding regulatory RNA spliced to about 1.5- and 2-kb introns that have regulatory roles on viral genes expression, and a 6.3-kb exon encoding multiple microRNAs, which target many of the IE genes and other lytic genes, thus suppressing viral replication [4][5][6][7][8][9][10]. It seems that LAT may be important for reactivation of HSV-1 from latency and for blocking apoptosis [11][12][13][14][15][16][17][18]. Periodically, HSV-1 will reactivate from latency due to stress, immunosuppression, or other stimuli, and newly produced virions will travel retrograde to the initial site of infection. There is currently no cure for HSV-1 and no vaccine.

There are three classes of viral genes for HSV-1 and they are expressed in a cascade fashion [19][20]. The virus first encodes the immediate-early (IE) or alpha (α) genes (ICP0, ICP4, ICP27, ICP22, or ICP47) whose products are important for expression of the next class of viral genes, the early (E) or beta (β) genes. The early genes encode proteins largely involved in viral DNA replication and, along with the immediate-early genes, facilitate the expression of the late class of viral genes. The late (L) or gamma (γ) class of viral genes express proteins involved in virion assembly and egress. HSV-1 genes are also divided based on stretches of unique sequences in the genome. Therefore, there are a class of unique long (UL) and unique short (US) genes depending on which region of the genome the gene is expressed from. These unique regions are flanked by inverted repeats. Thus, the HSV-1 genome is structured as follows: TRL-UL -IRL-IRS-US-TRS. There are about 58 UL genes and about 13 US genes that have been characterized for functionality, though there are more viral genes that have not been well characterized or described (Dolan 1998).

Interestingly, although HSV-1 is known to encode 80 genes, it has also been found that about half of these genes are non-essential for viral replication in cell culture [21][22]. Essential genes of HSV-1 are involved in viral DNA replication, the transcription of certain viral genes, genes encoding capsid proteins, genes encoding viral DNA packaging proteins, and some envelope glycoproteins. HSV-1 genes determined to be non-essential are involved in nucleic acid metabolism, combating various host responses to infection, facilitating optimal viral replication, facilitating primary envelopment, virus pathogenesis, or other functions that are not yet characterized (Table 1). While deletion of the non-essential genes in cell culture does not inhibit viral replication, these genes are generally essential for replication in the natural human host as mutant viruses deleted of non-essential genes have rarely been isolated from a patient. One example are mutants in the viral glycoprotein gC that have been recovered from patients with recurrent herpes keratitis [23][24].

Table 1. Non-essential genes of HSV-1, corresponding proteins, their location on the HSV-1 virion, and their function. Pink: tegument proteins, blue: accessory proteins, yellow: envelope proteins, green: capsid proteins.

Gene

Protein

Location on Virion

Function

RL1 or γ134.5

ICP34.5

tegument

Prevents host translational shutoff and autophagy

RL2 or α0

ICP0

tegument

Promiscuous transactivator of genes, disrupts repressor complexes, E3 ubiquitin ligase, inhibits innate immunity, modulates endocytosis, etc.

UL2

uracil-DNA glycosylase

accessory

nucleic acid metabolism

UL3

 

accessory

 

UL4

 

accessory

 

UL7

 

tegument

Virion assembly and egress

UL10

gM

envelope

Host and viral protein trafficking

UL11

 

tegument

Cytoplasmic envelopment

UL12

 

accessory

Nucleic acid metabolism

UL12.5

 

accessory

Involved in depleting mtDNA

UL13

Ser/thr protein kinase

tegument

Blocking innate immune responses, supporting viral protein synthesis

UL16

 

tegument

Cytoplasmic envelopment

UL20

 

envelope

Glycoprotein trafficking

UL21

 

tegument

Promotes capsid egress to the cytoplasm

UL23

thymidine kinase (TK)

tegument

Broad spectrum nucleoside kinase

UL24

 

accessory

Glycoprotein trafficking, nucleolus dispersal

UL31

 

accessory

Component of the nuclear egress complex (NEC), promotes primary nuclear envelopment

UL34

 

accessory

Component of the nuclear egress complex (NEC), promotes primary nuclear envelopment

UL35

VP26

capsid

Affects DNA packaging, mediates capsid assembly, trafficking post viral entry

UL39

RR1 (ribonucleotide reductase)

accessory

Part of the ribonucleotide reductase (RR) complex, converts ribonucleotide diphosphates to corresponding deoxyribonucleotides, allowing for virus replication particularly in non-dividing cells

UL40

RR2 (ribonucleotide reductase)

accessory

Part of the ribonucleotide reductase (RR) complex, converts ribonucleotide diphosphates to corresponding deoxyribonucleotides, allowing for virus replication particularly in non-dividing cells

UL41

VHS

tegument

Viral RNase, degrades host transcripts and blocks antiviral responses

UL43

 

tegument

 

UL44

gC

envelope

Mediates viral binding to heparan sulfate, regulates entry by a low-pH pathway

UL45

 

envelope

Required for syncytia formation during HSV-1 gB syn infection

UL46

VP11/12

tegument

Regulation of transcription, activates pathways for cell survival, blocks pathways for innate immunity activation

UL47

VP13/14

tegument

Regulation of transcription, modulating post-transcriptional processing of mRNAs

UL49

VP22

tegument

Facilitates viral gene expression, protein expression, and DNA replication; inhibits inflammasome

UL49.5

gN

envelope

Binding partner of gM

UL50

 

tegument

Nucleic acid metabolism

UL51

 

tegument

Participates in cytoplasmic envelopment; facilitates virus spread from cell-to-cell; recruits UL7 to tegument

UL53

gK

envelope

Participates in virion egress from host cell; regulates virus entry and fusogenic activity of the virion; complexes with UL20

UL55

 

tegument

Participates in cytoplasmic envelopment

UL56

 

tegument

Participates in cytoplasmic envelopment

US1

ICP22

accessory

Regulates viral late gene expression; facilitates formation of complexes important for protein folding; participates in primary envelopment; blocks immune responses

US1.5

 

accessory

Participates in viral gene transcription

US2

 

tegument

Protein trafficking

US3

Ser/thr protein kinase

tegument

Blocks apoptosis, enhances viral gene expression, facilitates capsid nuclear egress, phosphorylates numerous substrates

US3.5

Ser/thr protein kinase

tegument

Phosphorylates substrates but cannot block apoptosis and does not facilitate nuclear egress

US4

gG

envelope

Regulation of chemokines

US5

gJ

envelope

Inhibits apoptosis and cell stress pathways

US7

gI

envelope

Enhances virus spread from cell-to-cell; facilitates anterograde transport of virions after reactivation from latency; important for neurovirulence

US8

gE

envelope

Enhances virus spread from cell-to-cell; facilitates anterograde transport of virions after reactivation from latency; important for neurovirulence

US8.5

 

accessory

Localizes in the nucleoli

US9

 

tegument

Enhances virus spread from cell-to-cell; facilitates anterograde transport of virions after reactivation from latency; important for neurovirulence

US10

 

tegument

Important for neurovirulence

US11

 

tegument

Block PKR activation and shutoff of host translation; block IFN induction; regulation of virus genes expression; trafficking of unenveloped capsids

US12

ICP47

accessory

Prevents MHC I antigen presentation, supports neurovirulence

It is of great interest to understand the roles of non-essential genes to better understand virus–host interactions. Moreover, the non-essential genes have properties that make them attractive for the development of therapeutics. There are varying degrees of deficiency of viruses mutated for non-essential genes when grown in cell culture, and for some of these genes, the defect is cell type specific [25][26]. There is still much to learn about the non-essential genes of HSV-1. Here, we present a comprehensive analysis of the current understanding of the roles of non-essential genes of HSV-1. We explore the functions ascribed to these genes and their corresponding proteins, the potential treatment and therapeutic avenues that can be explored based on the functions and characterization of select HSV-1 non-essential genes, and the complex and intricate roles of non-essential genes in HSV-1 infection.

2. Repressors of Gene Silencing, Viral Transactivators, and Host Evasion Factors

2.1. RL2 or α0 (ICP0)

The infected cell protein 0 (ICP0) of HSV-1 was first reported as a nuclear phosphoprotein with an essential role in cell cultures only at low multiplicity of infection (MOI). ICP0 was deemed to be non-essential at high multiplicities of infection in cell cultures, but viral gene expression was reduced [19][27][28][29][30][31][32][33]. In certain cell lines, particularly cancer cell lines, such as the human osteosarcoma (U2OS), an ICP0-null virus replicates as efficiently as wild-type virus, which may be due to impaired recruitment of antiviral factors to the sites of viral gene transcription and DNA replication and/or due to lack of certain restriction factors [26][28][30][32][34][35]. Genes coding for ICP0 are present in the genomes of simplex and varicelloviruses, but they are absent from the mardivirus genus. These proteins show strong sequence homology to ICP0 within the RING (Really Interesting New Gene) finger domain. Orthologs of ICP0 are also present in lymphocryptoviruses (e.g., EBV) and the cytomegalovirus (CMV) [36][37][38]. The functions of ICP0 are broad, from activation of transcription and chromatin remodeling, to evasion of antiviral responses, cell cycle effects, interfering with DNA damage responses, and endocytosis.

In early studies, ICP0 was found with ICP4 to stimulate ICP8 expression in transfection assays [39][40]. Furthermore, it was shown to function as a potent transactivator of different genes introduced into cells by transfection or infection, including the viral thymidine kinase (TK) gene and ICP6 gene, the human immunodeficiency virus (HIV) LTR, and several human papillomavirus (HPV) genes [41][42][43][44][45][46][47][48][49][50]. In fact, ICP0 was found to stimulate the expression of all three classes of HSV genes [31][51]. Therefore, ICP0 was proposed to be a promiscuous transactivator of gene expression.

ICP0 also functions as an E3 ubiquitin ligase and most substrates ubiquitinated by ICP0 appear to be targeted for degradation (Figure 1A). This activity of ICP0 was mapped to residues 116-156, where there is a Zn2+-binding RING finger domain [52][53][54][55]. To exert its E3 ubiquitin ligase function, ICP0 forms a complex with different ubiquitin conjugation enzymes, including UbcH5a and UbcH6 [52][56][57][58][59][60]. Major targets of ICP0 are components of the nuclear domain 10 (ND10) bodies. As a DNA virus, the genome of HSV-1 transcribes and replicates in the nucleus. The host attempts to block viral gene expression and replication by entrapping the viral DNA in promyelocytic leukemia (PML)-nuclear bodies (NBs) and depositing histones and other repressor complexes on it. The main protein that orchestrates the formation of ND10 bodies is the PML. Other components of ND10s include the Sp100, Daxx, Mre 11, ATM, ATRX, p53, and others. ICP0 disrupts the ND10s by causing degradation of the different isoforms of PML, Sp100, and potentially of other proteins (Figure 1A) [34][59][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77] Notably, several components of the ND10 bodies are interferon inducible genes, which underscores the synergy between gene silencing mechanisms and innate immunity in suppressing HSV-1 gene expression. ICP0-null viruses or E3 ubiquitin ligase mutants have viral DNA entrapped in PML-NBs at low MOI and display reduced transactivation activity and ability to block antiviral responses [34][64][78][79][80][81][82][83]. ICP0 E3 ligase-deficient viruses are hypersensitive to interferon, replicate poorly, and fail to reactivate efficiently from neuronal latency [25][55][67][68][69][70][71]. Based, on these observations, Dr. Kalamvoki’s group recently developed a high-throughput assay to screen for ICP0-E3 ubiquitin ligases inhibitors [72]. This assay is proximity based and takes advantage of the fact that ICP0 is autoubiquitinated and degraded during infection and that this ICP0 autoubiquitination can occur in vitro using the purified protein encoded by the exon II of ICP0 (contains the RF domain), UbcH5a, and Ub [60][73][74]. Screening a small compound library, Dr. Kalamvoki’s group identified potential scaffolds that can interfere with the ICP0 E3 ubiquitin ligase activity [72].

ICP0 has seven SUMO-interacting motif (SIM)-like sequences (SLSs), and multiple ND10 components, including PML and SP100, are SUMOylated; therefore, ICP0 could bind to them (Figure 1A) [34][56][75][76][77][78][79][80][81]. It has been found that inhibition of cellular ubiquitination led to an increase of SUMOylated proteins that ended up accumulating at PML-NBs [82]. ICP0 utilizes both SUMO-dependent and SUMO-independent mechanisms to degrade Sp100 and multiple PML isoforms in an effort to prevent restriction of the virus by the host [34][56][75][76][78][79][83][84]. Other proteins could also be the target of SUMO-dependent degradation by ICP0 [75][77][81]. Specifically, SUMO-dependent degradation of MORC3 by ICP0, which associates with Sp100, has been observed and this occurs in a RING-finger-dependent manner and appears to diminish the association of PML-NBs with viral DNA [85]. Additionally, there has been a function ascribed to ICP0 SUMO–SIM interactions at the ND10s to modulate the DNA damage response (DDR) during infection [86][87]. For example, the DNA repair function of the DNA-dependent protein kinase (DNA-PK) is inhibited by ICP0 through degradation of its catalytic subunit and this facilitates virus replication [88][89][90]. Additionally, ICP0 mediates the degradation of two E3 ubiquitin ligases RFN8 and RFN168 that act as mediators of the ATM pathway and trigger recruitment of downstream effectors to sites of double-strand DNA breaks [91][92][93][94][95]. More work will need to be done to characterize the degradation of SUMOylated proteins by ICP0 that are not related to the ND10s. The ability for ICP0 to interrupt SUMO interactions and to degrade SUMOylated proteins during infection is likely a strategy to modify the cellular proteome to both prevent antiviral responses and promote the infection [34][76][83].

In tandem with the dispersion of ND10 bodies, ICP0 activates the viral chromatin (Figure 1B). Immediately after its release in the nucleus, HSV-1 DNA associates with repressive histones and other repressor complexes [96][97][98]. However, markers of active gene expression label the viral chromatin during lytic infection, such as tri-methylation of histone H3 at lysine 4 (H3K4) and acetylation of H3 at lysine 9 and lysine 14 [97][98][99], while suppressive epigenetic modifications of histone H3 (H3K9me3 and H3K27me3) are removed in an ICP0-dependent manner (Figure 1B) [65][100][101]. ICP0 was also found to associate with class II HDACs in vitro and control their repressor activity [102][103]. In addition, ICP0 seems to promote histone acetylation, as demonstrated using inhibitors of histone deacetylases [103][104][105]. This is also supported by the fact that ICP0 recruits to the viral genome the histone acetyltransferase CLOCK through interaction with the circadian regulator protein BMAL1. This leads to recruitment of additional viral transactivators ICP4, ICP22, ICP27, and part of the host transcription complex TFIID [106][107][108]. Tandemly, ICP0 disrupts repressor complexes, such as the REST/CoREST/HDAC complex and LSD1 [109][110][111][112]. ICP0 disperses the REST/CoREST/HDAC1/2/LSD1 through interaction with CoREST in an effort to promote HSV-1 gene expression and DNA replication (Figure 1B) [78][112][113][114][115]. It was also found that the interferon-inducible gene 16 (IFI16), Daxx, and ATRX proteins serve to restrict the virus, likely through sensing of viral DNA and obstructing replication and causing deposition of silencing histone H3 [34][65][100][116][117][118][119][120]. ICP0 induces the degradation of ATRX and IFI16 [121][122][123][124][125]. Degradation of ATRX seems to be secondary to PML degradation, while depletion of ICP0 appears to be both ICP0 dependent and independent.

ICP0 has also been shown to harness cell cycle components to support the infection. Thus, ICP0 was found to recruit cyclin D3 and the kinase cdk4 to ND10s to enable viral gene transcription and DNA replication, which was also supported by the fact that ICP0 nuclear-to-cytoplasmic translocation was enabled by cyclin D3 (Figure 1B) [108][126][127]. ICP0 has been found to arrest cells in the G2/M phase to promote virus replication by activating the checkpoint kinase 2 (Chk2) [128]. Consistent with these roles of ICP0, it was also found to degrade the centromere proteins CENP-A, CENP-B, and CENP-C, inducing the interphase centromere damage response (iCDR) (Figure 1A) [129][130][131][132]. In addition to this disturbance to the cell cycle, it has been found that ICP0 degrades the DNA-interacting protein TPP1, leading to transcription of telomere repeat-containing RNA activation (TERRA) and increased viral replication [133].

Figure 1. Nuclear functions of non-essential HSV-1 proteins. HSV-1 encodes multiple proteins able to counteract antiviral host responses within the nucleus. (A): ICP0 functions as an E3 ligase ubiquitin ligase that degrades ND10 components that encapsulate the viral genome in the nucleus, including PML, Daxx, SP100, centromeric proteins, and others. The degradation of IFI16 involves multiple factors. These events facilitate initiation of viral gene transcription. (B): The viral protein ICP0 is also known to disrupt repressor complexes that silence the viral genome, as well as recruit factors to enable viral gene transcription. Altogether, ICP0 facilitates permissive histone modifications, while suppressing silencing modifications, to enable for viral gene expression. (C): The viral kinases US3 and UL13, with ICP22, are known to facilitate viral late gene expression, which occurs through the recruitment of host factors, such as Topoisomerase IIα and RNA polymerase II, to the sites of DNA replication in the nucleus. Together, these non-essential viral proteins are important for optimal expression of other viral genes and for viral DNA replication.

As mentioned earlier, there are interwoven relationships between gene silencing and innate immunity and it is not coincidence the ICP0 targets them both. ICP0-null and other ICP0 mutant viruses displayed increased sensitivity to interferon both in vivo and in vitro [32][70][134][135]. As discussed above, ICP0 blocks the nuclear pattern recognition receptors (PRRs) IFI16 and DNA-PKs, which may also impact the cGAS and STING DNA sensing pathway [119][122][123][124][136][137]. Inhibition of STING-dependent immune responses involves ICP0 as ICP0-null virus growth is partially rescued in cells with impaired STING signaling [25][26]. Furthermore, ICP0 was found to reduce the levels of the Toll-like receptor 2 (TLR2) adaptors MyD88 (myeloid differentiation factor 88) and the Mal (MyD88 adaptor-like protein) TIRAP (TIR domain-containing adaptor protein), thus blocking immune responses through this pathway (Figure 2A) [138]. Overall, ICP0 has been proposed to inhibit IRF3 and IRF7-dependent immune responses to sequester these proteins away from host chromatin [139][140][141]. ICP0 was also recently found to have a role in autophagy inhibition through causing the downregulation of p62/SQSTM1 and OPTN autophagy adaptor proteins in a proteasome-dependent and RING finger-independent mechanism (Figure 2C) [142]. It was also demonstrated that the cytoplasmic ICP0 is most likely involved in this function. Another target of ICP0 is the deubiquitylating enzyme USP7 (ubiquitin-specific protease 7) or HAUSP. USP7 appears to bind and stabilize ICP0, but ICP0 degrades USP7 late during infection in a RING finger-dependent manner [58][78][79][143][144]. One reason why the virus could promote degradation of USP7 is because it has a major role in TLR- and TNFa receptor (TNFR)-induced gene expression [145].

Most functions of ICP0 discussed above are performed while in the nucleus. However, ICP0 translocates to the cytoplasm after enabling viral gene expression, where it remains for the reminder of the infection. The cytoplasmic functions of ICP0 remain unexplored. Dr. Roizman’s group first described an interaction of ICP0 with the endocytosis adaptor CIN85 [146]. Dr. Kalamvoki’s group has built upon these findings and reported that ICP0 promotes endocytosis of the viral entry receptor Nectin-1 (Figure 2A) [147]. This is perhaps a mechanism that ensures spread of progeny viruses to uninfected cells. CIN85 forms a complex with the Cbl E3 ligase that is involved in endocytosis of multiple surface components. Thus, ICP0 through CIN85 and Cbl could modulate the surface of infected cells to suppress antiviral responses.

Finally, the role of ICP0 has also been investigated during the latent stage of the virus. ICP0 appears to be important for efficient virus reactivation from latently infected trigeminal ganglia (TG) in mouse ocular infections [67][68][71][148][149][150][151]. ICP0 is also required for VP16-dependent viral reactivation [67][152]. While ICP0 is important for balancing lytic and latent infection, it is still not fully understood what its specific role is in this process.

Figure 2. Cytoplasmic functions of some non-essential HSV-1 proteins. (A): ICP0 participates in two major functions in the cytoplasm. First, ICP0 degrades the TLR2 adaptors TIRAP and Mal, thus blocking NF-κB activity. ICP0 also binds to the endocytosis adaptor CIN85 and along with Cbl promotes internalization of the viral entry receptor Nectin-1. This is a mechanism to promote progeny virus spread to uninfected cells. (B): The tegument protein UL46 blocks STING and TBK1, which prevents stimulation of interferon-regulated genes. ICP34.5 and US11 are also involved in blocking TBK1, emphasizing the importance of blocking TBK1 activity during HSV-1 infection. (C): The autophagy pathway is blocked during HSV-1 infection through binding of ICP34.5 to Beclin-1, thus preventing maturation of the autophagophore to an autophagosome. ICP0 has also been found to cause downregulation of p62 and OPTN proteins during infection, which may also serve as another mechanism of blocking selective autophagy. It has also been found that the protein encoded by UL12.5 causes depletion of mtDNA during infection, which causes damage to mitochondria. (D): HSV-1 prevents host translational shutoff from occurring during infection. One mechanism is through ICP34.5 binding to both PP1a and eIF2α, causing dephosphorylation of eIF2α and preventing shutoff of translation. HSV-1 also encodes vhs, which is a viral RNase that degrades AU-rich element (ARE) containing mRNAs. It has also been shown that vhs prevents the formation of cytoplasmic stress granules (SGs) during infection, which contain dsRNA that would otherwise cause PKR activation. HSV-1 also encodes US11, which blocks PKR, thus blocking host translational shutoff and innate immunity activation, as well as blocking PKR and PACT-induced activation of RIG-I during infection.

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Maria Kalamvoki
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