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Replicative Cycle of HHV8: History
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Contributor: Oana Manole ,
, Cristina Gales , Elena Porumb- Andrese , Otilia Obada

Around 12% of all cancers worldwide are caused by oncogenic viruses. Among these, only Kaposi’s sarcoma-associated herpesvirus (KSHV) and the human papillomavirus are an absolute requirement of oncogenesis for both their respectively determined cancers, and both are direct carcinogens. KSHV, also known as the Human gammaherpesvirus 8 (HHV8), is a double-stranded DNA and a Rhadinovirus, the only one of the genus with human tropism. HHV8 is found in all types of Kaposi’s sarcoma, and is needed for Kaposi’s sarcoma to appear, although the infection by itself is not enough. 

  • Kaposi’s sarcoma
  • immunosuppression
  • human herpes virus 8
  • skin cancer
  • angiogenesis

1. Latency Phase

During its latent phase, KSHV does not cause its host to exhibit any obvious signs of pathology [1]. After viral entry into the host’s cell, the latent phase starts and a very limited number of genes are expressed during this phase. The corresponding proteins of these genes are latency-associated nuclear antigen (LANA), viral interferon regulatory factor 3 (vIRF3/LANA2), vCyclin, viral FLICE inhibitory protein (vFLIP), kaposin and viral miRNAs [2][3][4]. They, along with their effects, are presented in Table 1 [2][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18].
Table 1. List of latent cycle expressed genes and their respective proteins.
Latent Cycle Gene—Protein Function
ORF73—LANA Serves as a means to circularize and attach the viral genome to the host’s chromosomes, but also inhibits p53 activity, tumor suppressor Rb, leads to progrowth proteins cyclin D and c-Myc upregulation and also extension of host cell life via telomerase expression.
ORF72—vCyclin Homologue of cellular Cyclin D. Can bind and activate the cyclin-dependent kinase cdk6 and through this complex lead to the inactivation of tumor suppressor retinoblastoma (Rb), cdk inhibitor p27 (Kip), and the antiapoptotic protein Bcl-2.
ORF71/K13—vFlip Is a homologue of caspase-8 inhibitory protein and has been shown to prevent the CD95 death receptor and cleavage of procaspase 8 (thus stopping the forming of active caspase 8).
ORFK12—Kaposins A, B and C Kaposins A, B and C; Kaposin A plays a role in cellular transformation and activation of the ERK/MAPK pathway. Kaposin B binds and activates the p38/MAPK target kinase MK2 inhibiting the decay of mRNAs such as those for PROX1, thus inducing the reprogramming of endothelial cells towards a lymphatic lineage
miRNAs ** Promotes cell survival via apoptosis inhibition, and continuation of latent phase, endothelial cell reprogramming, induction of migration and invasion (via miR-K12–3). miR-Ul112 downregulates MICB expression and reduces infected cell killing by natural killer cells; suppression of thrombospondin 1 (THBS1), a known tumor suppressor, leads to lowered TGB-β and subsequently leads to a loss of anti-angiogenic activity, contributing to carcinogenesis. miRNAs are present in all KSHV associated diseases (KS, Multicentric Castleman’s Disease (MCD) and primary effusion lymphoma (PEL), body cavity based cell lymphoma)
ORFK10.5—vIRF3/LANA2 Specific to B-cells. Inhibits p53 tumor suppressor. Expressed uniformly in PEL tumor cells. LANA2 inhibits cell cycle arrest mediated by 14-3-3σ overexpression.
ORF = open reading frame, named based on the homologous genes in Herpesvirus saimiri. K genes are unique to KSHV. ** miRNAs share the same gene locus as kaposins; however, they are transcribed as independent genes.

2. Reactivation and Lytic Phase

The lytic reactivation represents another critical step in tumorigenesis, as demonstrated by the finding that inhibition of the lytic cycle using Ganciclovir reduced the risk of developing KS by 75% [19]. The lytic cycle is thought to provide signals that stimulate proliferation of latent cells, and thus of the tumor. This phase of viral infection represents the expression of viral proteins, replication of the genome, and assembly of new virions by the host cell, which exit the cell via budding. Stimuli that start off the lytic cycle are not well defined, but the process can be induced by substances such as 12-O-Tetradecanoyl-phorbol-13-acetate (TPA), sodium butyrate [20], ionomycin [21] (a calcium ionophore), epinephrine and norepinephrine at physiological concentrations, certain cellular factors (X-box binding protein 1 (XBP-1), CREB-binding protein (CBP), the SWI/SNF chromatin remodeling complex, the TRAP/Mediator complex, RBP-Jκ, human Notch intracellular domain, and High mobility group box 1 (HMGB1)) [22][23][24][25][26][27][28], autonomic nervous system activity within AIDS patients [29], hypoxia [30], and reactive oxygen species (ROS) [31]. Recently, it was also demonstrated that nitric oxide (NO) plays an important role in proliferation of KSHV associated tumors and is necessary for the lytic phase. According to Herrera-Ortíz et al., suppression of NO results in a reduced level of infectious virions, lytic transcripts and proteins [32]. SARS-CoV-2 viral proteins, namely the S and N proteins, have been noted to induce lytic reactivation of KSHV, thus accelerating the oncogenic process [33]. Moreover, in the same study, Chen et al. also reported that some anti-COVID-19 drugs used as of the date of their study, such as Azithromycin and Nafamostat mesylate, also contribute to the lytic reactivation of KSHV, and that AIDS-KS tissues have a higher ACE2 receptor expression, although a clear link between KSHV and the upregulation has not been established [33]. CD147, a multifunctional glycoprotein upregulated during KSHV de novo infection and in Kaposi sarcoma tissues [34][35] also represents one of the co-receptors for SARS-CoV2 entry into host cells [36]. Other viruses may also trigger the reactivation of KSHV lytic cycle, such as HIV, herpes simplex virus type 1 (HSV-1), HSV-2, human cytomegalovirus (HCMV), human herpesvirus-6 (HHV-6) and HHV-7 [37][38][39][40][41]. Spindle cells, with typical spindle-shaped morphology, which are the tumor cells of KS, tend to segregate the latent viral genomes and, as such, lytic reactivation of small populations of cells must occur to maintain viral presence and latency [42].
Genes that are expressed in the lytic cycle are divided into three groups: immediate early (IE), early (E) and late (L) genes. The lytic phase genes of the IE and E groups of most relevance to KS are summarized in Table 2. Late genes mostly comprise viral structural components [43].
Table 2. Major genes expressed during lytic cycle and their functions.
Gene—Protein Function
ORF45—ORF45 (IE) Inhibits p53 signaling and prevents interaction with USP7 (a deubiquitinase), which results in diminished transcriptional activity [44].
ORFK4.2—ORFK4.2 (IE) Plays a role in immune evasion, lowering antibody-mediated adaptive immune responses [45].
ORFK12—Kaposins (E) Kaposin B has been shown to contribute to angiogenesis, reprogramming of endothelial cells, which has a proinflammatory effect via citokine upregulation [46][47][48][49][50].
ORF57—ORF57 (E) Interacts directly with PYM to facilitate the efficient translation of intronless KSHV mRNA transcripts [51]. Protects viral products such as viral interleukin-6 (vIL-6) and IL-6 from miRNA degradation [52].
K-bZIP (ORF-K8) (E) Modulator of RTA activity. Inhibits RTA autoactivation and transactivation of ORF57 and ORF-K15 [53].
K2—vIL-6 (E) Increased vascular endothelial growth factor a (VEGF-a) secretion (angiogenesis), tumor growth and plasmocytosis in mice [54].
K5—ubiquitin E3 ligases (E) Disruption of endothelial cell adhesion via cadherin downregulation [55].
K14—vOX-2 (E) Stimulates productions of inflammatory cytokines and chemokines, such as IL-1β, IL-6, tumor necrosis factor α (ΤNF-α), and monocyte chemoattractant protein-1 (MCP-1) [56].
K15—K15 (E) Vascular endothelial growth factor receptor (VEGFR) independent angiogenesis stimulation [57]. Stimulates endothelial cell proliferation and migration [58].
ORF16—vBcl2 (E) Essential to KSHV replication [59][60]. Anti-apoptotic and anti-autophagy evasion functions [61][62][63][64][65].
K1—K1 (E) Activation of the Phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, which leads to upregulation of protein synthesis and survival, while also inhibiting apoptotic signaling [66].
ORF74—vGPCR (E) Transformative properties [66]. Expression of vGPCR leads to immortalization of endothelial via VEGF receptor-2/KDR (kinase insert domain receptor) [67]. Knockdown of vGPCR is documented to lead to decreased tumor growth and lower secretion of VEGF in a mouse model [68].

This entry is adapted from the peer-reviewed paper 10.3390/diagnostics12051242

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