Abstract
Altered cell signaling is the molecular basis for cell proliferation occurring in association with several gamma herpesvirus infections. Three gamma herpesviruses, namely EBV/HHV-4, KSHV/HHV-8 and the MHV-68 (and/or MHV-72) and their unusual cell-pirated gene products are discussed in this respect. The EBV, KSHV as well as the MHV DNA may persist lifelong in an episomal form in the host carrier cells (mainly in lymphocytes but also in macrophages, in non-hornifying squamous epithelium and/or in blood vessel endothelial cells). Under conditions of extremely limited transcription, the EBV-infected cells express EBNA1 (EB nuclear antigen 1), the KSHV infected cells express LANA1 (latent nuclear antigen 1), while the MHV DNA carrier cells express the latency-associated protein M2. With the full set of latency-associated proteins expressed, EBV carrier cells synthesize additional EBNAs and at least one LMP (latent membrane protein 1). The latent KSHV carrier cells, in addition to LANA1, may express a viral cyclin, a viral Fas-DD-like ICE inhibitor protein (vFLIP) and a virus-specific transformation protein called kaposin (K12). In MHV latency with a wide expression of latency-associated proteins, the carrier cells express a LANA analogue (ORF73), the M3 protein, the K3/IE (immediate early) proteins and M11/bcl-2 homologue proteins. During the period of limited gene expression, the latency-associated proteins serve mainly for the maintenance of the latent episomal DNA (a typical example is EBNA1). In contrast, during latency with a broader spectrum gene expression, the virus-encoded products activate transcription of otherwise silenced cellular genes, which leads to the synthesis of enzymes capable of promoting not only viral but also cellular DNA replication. Thus, the latency-associated proteins block apoptosis and drive host cells towards division and immortalization. Proliferation of hemopoetic cells, which had become gamma herpesvirus DNA carriers, can be initiated and strongly enhanced in the presence of inflammatory cytokines and by virus-encoded analogues of interleukins, chemokines and IFN regulator proteins. At early stages of tumor formation, many proliferating hemopoetic and/or endothelium cells, which had became transcriptionally active under the influence of chemokines and cytokines, may not yet be infected. In contrast, at later stages of oncogenesis, the virus-encoded proteins, inducing false signaling and activating the proliferation pathways, bring the previously infected cells into full transformation burst.
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Abbreviations
- AIDS:
-
acquired immunodeficiency virus
- AM:
-
adherent mononuclear (cells)
- Apo1:
-
apoptosis receptor 1 (Fas receptor)
- ART:
-
activator of replication and transcription
- BL:
-
Burkitt’s lymphoma
- BRLF:
-
BamHI R leftward fragment (EBV DNA)
- BZLF:
-
BamHI Z leftward fragment (EBV DNA)
- CD:
-
cluster of differentiation (leukocyte marker)
- cdk:
-
cyclin-dependent kinases
- c-jun:
-
cellular ju-nana (japanese expression for 17 sarcoma virus)
- CMV:
-
cvtomegalovirus
- CNS:
-
centraf nervous system
- CREB:
-
(cAMP-response element)-binding protein
- CTAR:
-
C-terminal activator regions
- DD:
-
death domain
- DED:
-
death effector domain
- DS:
-
dyad symmetry (EBV DNA region)
- EBER:
-
Epstein—Barr encoded nonpolyadenylated RNA
- EBNA:
-
Epstein—Barr nuclear antigen
- EBV:
-
Epstein—Barr virus
- FADD:
-
Fas receptor-associated death domain
- Fas:
-
FS-7 associated cell surface (protein)
- FGARAT:
-
N-formylglycinamide ribotide aminotransferase
- FLICE:
-
FADD-like interleukin converting enzyme inhibitor protein (vFLIP)
- FR:
-
family of repeats
- GAS:
-
gamma-activated sequence
- GPCR:
-
G-protein coupled receptor
- HAX-1:
-
HS-1 associated protein X-1
- HHV:
-
human herpesvirus
- HIV:
-
human immunodeficiency virus
- HL:
-
Hodgkin’s lymphoma
- HLA:
-
human leukocyte antigen
- HS-1:
-
hemopoetic specific protein 1
- HSV-1:
-
herpes simplex virus 1
- HVS:
-
herpesvirus saimiri
- ICE:
-
interleukin-1β converting enzyme
- IE:
-
immediate early proteins
- IFN:
-
interferon
- IKK:
-
inactivator kinases
- IL:
-
interleukin
- IM:
-
infectious mononucleosis
- IRF:
-
IFN regulating factor
- IS:
-
immunosuppression
- ITAM:
-
immunoreceptor tyrosine-based activator motif
- K-bZIP:
-
KSHV analogue of the EBV-specified Zta
- KIP/CIP:
-
kinase inhibitor protein/cyclin inhibitor protein
- KS:
-
Kaposi’s sarcoma
- KSHV:
-
Kaposi’s sarcoma (associated) herpesvirus
- LANA:
-
latent nuclear antigen
- LCL:
-
lymphoblastoid cell lines
- LMP:
-
latent membrane protein
- LPD:
-
lymphoproliferative disorders
- LTP:
-
large tegument protein
- MAPK:
-
mitogen activated protein kinase
- MapK/MKK:
-
mitogen activated kinase/kinase cascade
- MCD:
-
multicentric Castleman disease
- MCP:
-
monocyte chemoattractant proteins
- MHV:
-
murine herpesvirus
- NFAT:
-
nuclear factor activator of T cells
- NF-κB:
-
nuclear factor κB
- NIK:
-
NF-κB inducing kinase
- NPC:
-
nasopharyngeal carcinoma
- OBP:
-
ori-binding protein
- PAN:
-
polyadenylated nuclear RNA species
- PEL:
-
primary effusion lymphoma
- Rb:
-
retinoblastoma (proteins)
- RR:
-
ribonucleotide reductase (genes)
- RS:
-
Reed—Sternberg (cells)
- Rta:
-
R transactivator protein (R fragment encoded)
- Sos:
-
son of sevenless (protein)
- STAT:
-
signaling transduction and transcription
- TK:
-
thymidine kinase
- TNF:
-
tumor necrosis factor
- TNFR:
-
TNF receptor
- TPA:
-
4β,9α,12β,13α,20-pentahydroxytiglia-1,6-dien-3-one 12β-myristate 13α-acetate (‘12-O-tetradecanoylphorbol 13-acetate’)
- TRADD:
-
TNFR-associated death domain
- TRAF:
-
TNFR-associated factor
- vCyclin:
-
viral cyclin
- VEGF:
-
vascular endothelial growth factor
- vFLIP:
-
viral FLICE (caspase 1) inhibitor protein
- vGPCR:
-
viral G-protein coupled receptor
- vMIP:
-
viral macrophage inflammatory protein
- VZV:
-
varicella zoster virus
- Zta:
-
Z (‘Zebra’) transactivator protein (Z fragment encoded)
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Rajčáni, J., Kúdelová, M. Gamma herpesviruses: Pathogenesis of infection and cell signaling. Folia Microbiol 48, 291–318 (2003). https://doi.org/10.1007/BF02931360
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DOI: https://doi.org/10.1007/BF02931360