Kaposi's sarcoma-associated herpesvirus
Human gammaherpesvirus 8 | |
---|---|
Kaposi's sarcoma | |
Virus classification | |
(unranked): | Virus |
Realm: | Duplodnaviria |
Kingdom: | Heunggongvirae
|
Phylum: | Peploviricota |
Class: | Herviviricetes |
Order: | Herpesvirales |
Family: | Orthoherpesviridae
|
Genus: | Rhadinovirus |
Species: | Human gammaherpesvirus 8
|
Kaposi's sarcoma-associated herpesvirus (KSHV) is the ninth known human
History
In 1872,
Careful analysis of epidemiologic data by Valerie Beral, Thomas Peterman and Harold Jaffe,
As early as 1984, scientists reported seeing herpesvirus-like structures in KS tumors examined under
The discovery of this
Virology
KSHV is a
Crucial for the entry of KSHV into cells [13] are the EPH receptor A2,[14] Hrs,[15] TSG101,[16] and a few integrins (whose identity has yet to be confirmed).[17] After infection, the virus enters into lymphocytes via macropinosomes.[citation needed] Once the virus newly infects a cell, the lipid membrane is shed and the virion travels to the nucleus. The viral genome is released where it circularizes into an episome through a poorly understood process that appears to involve homologous recombination of the terminal repeats.[citation needed] The viral episome is chromatinized upon entry into the host cell nucleus.[18]
After entry, the virus typically remains in a latent ("quiet") state. Only a subset of genes that are encoded in the KSHV latency associated region (KLAR) are expressed during latency, including latency-associated nuclear antigen (LANA), vFLIP, vCyclin and 12 microRNAs. Latency is the hallmark of all KSHV-associated etiologies known to date including all KSHV-associated oncogenesis. It has been shown that both protein coding genes such as LANA and noncoding genes (microRNAs) encoded in KLAR are important for KSHV associated tumorigenesis. To study the functions of microRNAs, a detailed protocol of bacmid mutagenesis and a complete set of cell-lines carrying microRNA deletion mutants have been established and are available as a resource to researchers.[19] Additionally, it has been shown that vFLIP and vCyclin interfere with the TGF-β signaling pathway indirectly by inducing the oncogenic host mir17-92 cluster.[20] These observations represents a novel mechanism that may be important for KSHV tumorigenesis and angiogenesis, a hallmark of KS.[citation needed]
During latency, LANA is the only viral protein that is required for viral replication, which is carried out by the host replication machinery. LANA tethers the viral DNA to cellular chromosomes, inhibits
Various signals such as inflammation may provoke the virus to enter into lytic replication. The primary viral protein responsible for the switch between latent and lytic replication is known as the ORF50 Replication Transactivation Activator (RTA). When cell signaling conditions activate the generation of RTA, it in turn activates synthesis of a stereotypic cascade of secondary and tertiary viral proteins that ultimately make components of the virus capsid and also the DNA synthesis enzymes required to replicate the virus genome.[22] During lytic replication, it is believed that the virus genome is replicated as a continuous linear molecule off of an episome (so-called rolling circle model). As each unit genome is replicated, it is cut within the terminal repeat region, and then packaged into a virus particle (virion). The virus then becomes enveloped with a lipid membrane as it transits the nucleus and the cytoplasm to exit the cell. Thus, whereas KSHV genome is circular in the nucleus of latently infected cells, it is packaged into infectious viruses as a linear molecule. When the virus enters into lytic replication, thousands of virus particles can be made from a single cell, which usually results in death of the infected cell.[citation needed]
COVID-19 and KSHV
It was discovered in 2020 that infection with the SARS-CoV-2 virus, the virus which causes COVID-19, may induce the lytic reactivation of KSHV in the human body, causing the herpes virus to cease latency and begin the formation of cancerous cells. Further, it was discovered that some medications used to treat the infection with SARS-CoV-2, namely Nafamostat and Azithromycin, ended up promoting the production of mature virions, "... potentially inducing KSHV lytic reactivation."[23]
Pathophysiology
The mechanisms by which the virus is contracted are not well understood. Healthy individuals can be infected with the virus and show no signs or symptoms, due to the immune system's ability to keep the infection in check. Infection is of particular concern to the immunocompromised. Cancer patients receiving chemotherapy, AIDS patients, and organ transplant patients are all at a high risk of showing signs of infection.[citation needed].
Recent advances in sequencing technologies have uncovered that virus is chromatinized during latency. It has also been shown that virus encoded microRNA manipulates and interacts not only with host mRNA but also deregulate host long non-coding RNA (lncRNA).[24] More recently, circularRNAs (circRNAs) are recently discovered in both EBV and KSHV [25][26][27]
Infection with this virus is thought to be lifelong, but a healthy immune system will keep the virus in check. Many people infected with KSHV will never show any symptoms. Kaposi's sarcoma occurs when someone who has been infected with KSHV becomes immunocompromised due to AIDS, medical treatment, or, very rarely, aging.
KSHV is a known causative agent of four diseases:[4][28]
- Kaposi's sarcoma – an angioproliferative tumor that can involve skin (most often), lymph nodes, or viscera,
- lymphoproliferative disorder,
- Primary effusion lymphoma – KSHV-associated aggressive lymphoma involving B-cells that are immature plasma cells termed plasmablasts and regarded as one type of lymphoid neoplasms with plasmablastic differentiation,
- KSHV inflammatory cytokine syndrome – a syndrome with MCD-like symptoms but without associated pathology.
Epidemiology
In the 1970s, the global prevalence rate for HHV-8 was 2 to 10%.
In countries with low seroprevalence, HHV-8 is primarily limited to AIDS and KS patients.[39] In countries with high seroprevalence, infection is frequent in childhood,[40] indicating a likely mother-to-child transmission by saliva.[41][42] In a Zambian survey, all children with KS had mothers who were positive for HHV-8, whereas not all children whose mothers had KS were HHV-8 positive.[43] In another Zambian survey, 13.8% of children were seropositive for HHV-8 by age 4.[44] Seroprevalence has not been shown to vary significantly because of gender or marital status.[36]
Evolution
The most recent common ancestor of this virus in the Mediterranean, Iran, and Xinjiang, China, has been estimated to have evolved 29,872 years (95% highest probability density 26,851–32,760 years) ago.[45] the most recent common ancestor for viruses isolated in Xinjiang was 2037 years (95% highest probability density 1843–2229 years) ago. Given the historical links between the Mediterranean and Xinjiang during the Roman period it seems likely that this virus was introduced to Xinjiang along the Silk Road. The mutation rate was estimated to be 3.44×10−6 substitutions per site per year (95% highest probability density 2.2×10−6 to 4.71×10−6). However, the global distribution of different genotypes of KSHV and the potential transmission path need further studies.[citation needed]
Typing of isolates is based on the variable K1 membrane protein. Six types are recognised (A–F).[46]
Prevention
Since persons infected with KSHV will asymptomatically give the virus, caution should be used by
Treatment
Kaposi's sarcoma is usually a localized tumor that can be treated either surgically or through local irradiation. Chemotherapy with drugs such as liposomal
Although KSHV affects the host immune system, there is ample chance for clinical intervention to recover this change. One challenge is overexpression inhibitory of target cell repress immune. Under longtime inflammation stimulation, the target cell becomes unable to respond, which leads to an exhausted phenotype. The activation immunotherapies can revive and enhance immune cell function. Comparing to other immunotherapies, therapies targeting the anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) has been a great success. Because of KSHV infection, the monocytes increase the expression of PD-1, which is an inhibitory molecule, and cause immune escape in many tumor types. There is high PD-1 expression in NK cells from KS-HIV patients and cause exhausted phenotype. The anti-PD-1 antibody, (nivolumab or pembrolizumab), demonstrated a significant antitumor effect. Nivolumab is currently an ongoing phase I clinical trial, and Pembrolizumab has shown its function in treatment for HIV and KS patients in phase I and is in a phase II trial for treatment. A thalidomide analog medicine – Pomalidomide was also granted by the FDA in 2011. Pomalidomide was shown to recover the expression of MHC-1, which help cell display intracellular proteins to cytotoxic T cells, and it also can repress the expression of PD-L1 and increase the CD8+ T cell killing.[49]
KSHV genes
KSHV encodes for ~90 genes and multiple non-coding RNAs, such as microRNAs.[50] The "ORF" genes are named based on genome position of the homologous genes in the first rhadinovirus described, herpesvirus saimiri. The "K" genes are unique to KSHV, Some KSHV genes have well-characterized functions, while others remain uncharacterized.[citation needed]
ORF2 – dihydrofolate reductase
ORF8 – gB – envelope glycoprotein involved in viral entry
ORF9 – Pol8 – DNA polymerase required for viral DNA replication
ORF10 – regulates RNA export and responses to type I IFNs
ORF16 – v
ORF18, ORF24, ORF30, ORF31, ORF34, ORF66 – viral transcription factors required for the expression of late genes
ORF21 – vTK – thymidine kinase
ORF22 – gH – envelope glycoprotein involved in viral entry
ORF23 – uncharacterized
ORF25, ORF26 and ORF65 – capsid proteins
ORF33 – involved in viral particle formation
ORF34 – unclear function
ORF35 – unclear function, mutant does not express early viral genes
ORF36 – vPK – viral protein kinase with multiple roles in replication cycle
ORF37 – SOX – dual function protein – DNase activity required for genome packaging and RNase activity regulates host gene expression
ORF38 – involved in viral particle formation
ORF39 – gM – envelope glycoprotein
ORF40 and ORF41 – helicase and primase – DNA replication
ORF42 – uncharacterized
ORF45 – tegument protein, binds and prevents dephosphorylation of p90 ribosomal S6 kinases (RSKs) and ERK for modulate the ERK/RSK MAPK signaling pathway
ORF47 – gL – envelope glycoprotein involved in viral entry
ORF49 – may be required for viral gene expression
ORF50 – RTA, replication and transcription activator – the major transcription factor driving lytic KSHV reactivation
ORF52 – KicGAS – tegument protein required for formation of virions and inhibition of cGAS DNA sensing
ORF53 – gN – envelope glycoprotein
ORF55 – uncharacterized
ORF57 – MTA – regulates RNA stability, export and translation of viral genes
ORF59 – PF–8 – polymerase processivity factor, accessory subunit of viral DNA polymerase
ORF67 and ORF69 – nuclear egress
ORF70 – thymidylate synthase
ORF72 – vCyclin
ORF73 – LANA, latency-associated nuclear antigen– tethers genome to chromosome during latency, also regulates host gene expression. A cytoplasmic form of LANA may inhibit activation of immune responses.
ORF74 – vGPCR
ORF75 – FGARAT
PAN,
K1 – involved in oncogenesis
K2 – Interleukin 6 homolog, Q2HRC7
K3 and K5 –
K4 – vCCL2 – chemokine
K4.1 – vCCL3 – chemokine
K8 – transcriptional repressor – modulates chromatin
K8.1 – envelope glycoprotein
K9 – v
K10 – v
K10.5 – v
K11 – v
K12 – kaposin
K13 – vFLIP
See also
- Oncovirus (cancer virus)
- Smoker's paradox
References
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Further reading
- Edelman DC (2005). "Human herpesvirus 8 – A novel human pathogen". Virology Journal. 2: 78. PMID 16138925.
External links
- Human Herpesvirus-8: Related Resources HIV InSite
- KSHV Annual Workshop 22nd International Workshop on Kaposi Sarcoma Herpesvirus (KSHV) and Related Agents, 30 June – 3 July 2019, New York City, USA