Kaposi's sarcoma-associated herpesvirus (KSHV) is the ninth known human
herpesvirus
''Orthoherpesviridae'', previously named and more widely known as ''Herpesviridae'', is a large family of DNA viruses that cause infections and certain diseases in animals, including humans. The members of this family are commonly known as herp ...
. It is also called Human herpesvirus 8, or HHV-8 in short. This virus causes
Kaposi's sarcoma
Kaposi's sarcoma (KS) is a type of cancer that can form masses on the skin, in lymph nodes, in the mouth, or in other organs. The skin lesions are usually painless, purple and may be flat or raised. Lesions can occur singly, multiply in a limite ...
, a cancer commonly occurring in
AIDS
The HIV, human immunodeficiency virus (HIV) is a retrovirus that attacks the immune system. Without treatment, it can lead to a spectrum of conditions including acquired immunodeficiency syndrome (AIDS). It is a Preventive healthcare, pr ...
patients,
as well as
primary effusion lymphoma
Primary or primaries may refer to:
Arts, entertainment, and media Music Groups and labels
* Primary (band), from Australia
* Primary (musician), hip hop musician and record producer from South Korea
* Primary Music, Israeli record label
Work ...
,
HHV-8-associated multicentric Castleman's disease and
KSHV inflammatory cytokine syndrome.
[ It is one of seven currently known human cancer viruses, or ]oncovirus
An oncovirus or oncogenic virus is a virus that can cause cancer. This term originated from studies of acutely transforming retroviruses in the 1950–60s, when the term ''oncornaviruses'' was used to denote their RNA virus origin. With the let ...
es. Even after many years since the discovery of KSHV/HHV8, there is no known cure for KSHV associated tumorigenesis.
History
In 1872, Moritz Kaposi
Moritz Kaposi (, ; 23 October 1837 – 6 March 1902) was a physician and dermatologist from the Austro-Hungarian Empire who discovered the skin tumor that received his name (Kaposi's sarcoma).
Biography
Early life and name
Born in Kaposvár, ...
described a blood vessel tumor (originally called "idiopathic multiple pigmented sarcoma of the skin") that has since been eponymously named Kaposi's sarcoma
Kaposi's sarcoma (KS) is a type of cancer that can form masses on the skin, in lymph nodes, in the mouth, or in other organs. The skin lesions are usually painless, purple and may be flat or raised. Lesions can occur singly, multiply in a limite ...
(KS). KS was at first thought to be an uncommon tumor of Jewish and Mediterranean populations until it was later determined to be extremely common throughout sub-Saharan African populations. This led to the first suggestions in the 1950s that this tumor might be caused by a virus. With the onset of the AIDS
The HIV, human immunodeficiency virus (HIV) is a retrovirus that attacks the immune system. Without treatment, it can lead to a spectrum of conditions including acquired immunodeficiency syndrome (AIDS). It is a Preventive healthcare, pr ...
epidemic in the early 1980s, there was a sudden resurgence of KS affecting AIDS patients, with up to 50% of reported AIDS patients having this tumor—an extraordinary rate of cancer predisposition.
Careful analysis of epidemiologic data by Valerie Beral, Thomas Peterman and Harold Jaffe
Harold Jaffe (July 8, 1938 – June 23, 2024) was an American writer of novels, short fiction, drama, and essays. He was the author of 30 books, including 14 collections of fiction, four novels, and two volumes of essays. He was also the editor ...
, led these investigators to propose that KS is caused by an unknown sexually transmitted virus that rarely causes tumors unless the host becomes immunosuppressed
Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse react ...
, as in AIDS.
As early as 1984, scientists reported seeing herpesvirus-like structures in KS tumors examined under electron microscopy
An electron microscope is a microscope that uses a beam of electrons as a source of illumination. It uses electron optics that are analogous to the glass lenses of an optical light microscope to control the electron beam, for instance focusing i ...
. Scientists had been searching for the agent causing KS, and over 20 agents were proposed as the possible cause, including cytomegalovirus
''Cytomegalovirus'' (CMV) (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order '' Herpesvirales'', in the family '' Herpesviridae'', in the subfamily '' Betaherp ...
and HIV
The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the im ...
itself. The pathogen was ultimately identified in 1994 by Yuan Chang and Patrick S. Moore, a wife and husband team at Columbia University
Columbia University in the City of New York, commonly referred to as Columbia University, is a Private university, private Ivy League research university in New York City. Established in 1754 as King's College on the grounds of Trinity Churc ...
, through the isolation of DNA fragments from a herpesvirus
''Orthoherpesviridae'', previously named and more widely known as ''Herpesviridae'', is a large family of DNA viruses that cause infections and certain diseases in animals, including humans. The members of this family are commonly known as herp ...
found in a KS tumor in an AIDS patient. Chang and Moore used representational difference analysis, or RDA, to find KSHV by comparing KS tumor tissue from an AIDS patient to his own unaffected tissue. The idea behind this experiment was that if a virus causes KS, the genomic DNA in the two samples should be precisely identical except for DNA belonging to the virus. In their initial RDA experiment, they isolated two small DNA fragments that represented less than 1% of the actual viral genome. These fragments were similar (but still distinct from) the known herpevirus sequences, indicating the presence of a new virus. Starting from these fragments, this research team was then able to sequence the entire genome of the virus less than two years later.
The discovery of this herpesvirus
''Orthoherpesviridae'', previously named and more widely known as ''Herpesviridae'', is a large family of DNA viruses that cause infections and certain diseases in animals, including humans. The members of this family are commonly known as herp ...
sparked considerable controversy and scientific in-fighting until sufficient data had been collected to show that indeed KSHV was the causative agent of Kaposi's sarcoma. The virus is now known to be a widespread infection of people living in sub-Saharan Africa; intermediate levels of infection occur in Mediterranean populations (including Lebanon, Saudi Arabia, Italy, and Greece) and low levels of infection occur in most Northern European and North American populations. The incidence rate is higher among gay and bisexual men.
Virology
KSHV is a herpesvirus
''Orthoherpesviridae'', previously named and more widely known as ''Herpesviridae'', is a large family of DNA viruses that cause infections and certain diseases in animals, including humans. The members of this family are commonly known as herp ...
, and is a large double-stranded DNA virus with a protein covering that packages its nucleic acids, called the capsid
A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or m ...
, which is then surrounded by an amorphous protein layer called the tegument
Tegument may refer to:
* Integumentary system, a protective organ system forming the outermost layer of an animal's body
* Tegument (helminth), an outer covering characteristic of flatworms
* Viral tegument
A viral tegument or tegument, more ...
, and finally enclosed in a lipid envelope derived in part from the cell membrane. KSHV has a genome
A genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding genes, other functional regions of the genome such as ...
which is approximately 165,000 nucleic acid bases in length. The viral genome consists of a ~145 kilobase
A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...
-long unique region, encoding all of expressed viral genes, which is flanked by ~20-30 kilobases of terminal repeat sequences.
Each terminal repeat unit is 801 bp in length, has 85% G+C content and is oriented in a repetitive head-to-tail fashion. KSHV is a rhadinovirus
''Rhadinovirus'' (synonyms: ''Rhadinoviridae'' and gamma-2 herpesviruses) is a genus of viruses in the order ''Herpesvirales'', in the family ''Herpesviridae'', in the subfamily ''Gammaherpesvirinae''. Humans and other mammals serve as natural h ...
, a Herpes genus remarkable since it has stolen numerous genes from host cells including, in the case of KSHV, genes that encode for complement
Complement may refer to:
The arts
* Complement (music), an interval that, when added to another, spans an octave
** Aggregate complementation, the separation of pitch-class collections into complementary sets
* Complementary color, in the visu ...
-binding protein, IL-6, BCL-2
Bcl-2, encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins. BCL2 blocks programmed cell death (apoptosis) while other BCL2 family members can either inhibit or induce it. It was the first a ...
, cyclin
Cyclins are proteins that control the progression of a cell through the cell cycle by activating cyclin-dependent kinases (CDK).
Etymology
Cyclins were originally discovered by R. Timothy Hunt in 1982 while studying the cell cycle of sea urch ...
-D, a G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...
, interferon regulatory factor
Interferon regulatory factors (IRF) are proteins which regulate transcription of interferons (see regulation of gene expression). Interferon regulatory factors contain a conserved N-terminal region of about 120 amino acids, which folds into a s ...
and Flice inhibitory protein ( FLIP), as well as DNA synthesis proteins including dihydrofolate reductase
Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in one-carbon transfer chemistry. ...
, thymidine kinase
Thymidine kinase is an enzyme, a phosphotransferase (a kinase): 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21. It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Cert ...
, thymidylate synthetase
Thymidylate synthase (TS) () is an enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thymidine is one of the nucleotides in DNA. With inhibition of TS, an imbalance of deoxynucleot ...
, DNA polymerase
In biochemistry, a polymerase is an enzyme (Enzyme Commission number, EC 2.7.7.6/7/19/48/49) that synthesizes long chains of polymers or nucleic acids. DNA polymerase and RNA polymerase are used to assemble DNA and RNA molecules, respectively, by ...
and many others. While no other human tumor virus possesses these same genes, other tumor viruses target the same cellular pathways illustrating that at a basic level, all tumor viruses appear to attack the same cellular control pathways, so-called tumor suppressor pathways.
Crucial for the entry of KSHV into cells
are the EPH receptor A2
EPH receptor A2 (ephrin type-A receptor 2) is a protein that in humans is encoded by the ''EPHA2'' gene.
Function
This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have bee ...
,
Hrs,
TSG101
Tumor susceptibility gene 101, also known as TSG101, is a human gene that encodes for a cellular protein of the same name.
Function
The protein encoded by this gene belongs to a group of apparently inactive homologs of ubiquitin-conjugating enz ...
,
and a few integrin
Integrins are transmembrane receptors that help cell–cell and cell–extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, o ...
s (whose identity has yet to be confirmed).
After infection, the virus enters into lymphocytes
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), and ...
via macropinosome
Macropinosomes are a type of cellular compartment that form as a result of macropinocytosis.
Formation
Macropinosomes have been described to form via a wave-like mechanism or via a tent-pole formation both of which processes require rapid polym ...
s.
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
An episome is a special type of plasmid, which remains as a part of the eukaryotic genome without integration. Episomes manage this by replicating together with the rest of the genome and subsequently associating with metaphase chromosomes during m ...
through a poorly understood process that appears to involve homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in Cell (biology), cellular organi ...
of the terminal repeats. The viral episome is chromatinized upon entry into the host cell nucleus.
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.
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. These observations represents a novel mechanism that may be important for KSHV tumorigenesis and angiogenesis, a hallmark of KS.
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 p53
p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...
and retinoblastoma protein
Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and 80% of retinoblastoma cas ...
and suppresses viral genes needed for full virus production and assembly ("lytic replication"). Why only a subset of virus genes expressed during latency is not fully understood. But it has been shown that the latency associated gene expression can be explained in part by a characteristic epigenetic
In biology, epigenetics is the study of changes in gene expression that happen without changes to the DNA sequence. The Greek prefix ''epi-'' (ἐπι- "over, outside of, around") in ''epigenetics'' implies features that are "on top of" or "in ...
state that KSHV episome acquires during latency. LANA plays an important role during latency, regulating both host and virus transcripts and binding to multiple active promoters; it also associates with the host protein hSET1 that creates H3K4me3
H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates tri-methylation at the 4th lysine residue of the histone H3 protein and is often involved in the regulation of gene expression. The name denotes the addit ...
marks in chromatin.
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.
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.
COVID-19 and KSHV
It was discovered in 2020 that infection with the SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19, the respiratory illness responsible for the COVID-19 pandemic. The virus previously had the Novel coronavirus, provisional nam ...
virus, the virus which causes COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by the coronavirus SARS-CoV-2. In January 2020, the disease spread worldwide, resulting in the COVID-19 pandemic.
The symptoms of COVID‑19 can vary but often include fever ...
, 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 infection with SARS-CoV-2, namely Nafamostat and Azithromycin
Azithromycin, sold under the brand names Zithromax (in oral form) and Azasite (as an eye drop), is an antibiotic medication used for the treatment of several bacterial infections. This includes otitis media, middle ear infections, strep throa ...
, ended up promoting the production of mature virions, "... potentially inducing KSHV lytic reactivation."
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
Immunodeficiency, also known as immunocompromise, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that affe ...
. Cancer patients receiving chemotherapy, AIDS patients, and organ transplant patients are all at a high risk of showing signs of infection..
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). More recently, circularRNAs (circRNAs) are recently discovered in both EBV and KSHV
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:
* Kaposi's sarcoma
Kaposi's sarcoma (KS) is a type of cancer that can form masses on the skin, in lymph nodes, in the mouth, or in other organs. The skin lesions are usually painless, purple and may be flat or raised. Lesions can occur singly, multiply in a limite ...
– an angioproliferative tumor that can involve skin (most often), lymph nodes, or viscera,
* HHV-8-associated multicentric Castleman's disease – a lymphoproliferative disorder
Lymphoproliferative disorders (LPDs) refer to a specific class of diagnoses, comprising a group of several conditions, in which lymphocytes are produced in excessive quantities. These disorders primarily present in patients who have a compromised ...
,
* Primary effusion lymphoma
Primary or primaries may refer to:
Arts, entertainment, and media Music Groups and labels
* Primary (band), from Australia
* Primary (musician), hip hop musician and record producer from South Korea
* Primary Music, Israeli record label
Work ...
– KSHV-associated aggressive lymphoma involving B-cells that are immature plasma cell
Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells and secrete large quantities of proteins called antibodies in response to being presented specific substances ca ...
s 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%. The seroprevalence of HHV-8 varies significantly geographically and infection rates in northern European, southeast Asian, and Caribbean countries are between 2-4%, in Mediterranean countries at approximately 10%, and in sub-Saharan African countries at approximately 40%. In South America, infection rates are low in general but are high among Amerindian
In the Americas, Indigenous peoples comprise the two continents' pre-Columbian inhabitants, as well as the ethnic groups that identify with them in the 15th century, as well as the ethnic groups that identify with the pre-Columbian population of ...
s. Even within individual countries, significant variation can be observed across different regions, with infection rates of about 19.2% in Xinjiang
Xinjiang,; , SASM/GNC romanization, SASM/GNC: Chinese postal romanization, previously romanized as Sinkiang, officially the Xinjiang Uygur Autonomous Region (XUAR), is an Autonomous regions of China, autonomous region of the China, People' ...
compared to about 9.5% in Hubei
Hubei is a province of China, province in Central China. It has the List of Chinese provincial-level divisions by GDP, seventh-largest economy among Chinese provinces, the second-largest within Central China, and the third-largest among inland ...
, China. Although seroprevalence has been consistently shown to increase with age in a linear manner, countries with high infection rates may see higher seroprevalence in younger age groups. Educational level has shown an inverse correlation with infection rates. Individuals infected with HIV-1 or genital warts are generally more likely to be co-infected with HHV-8.
In countries with low seroprevalence, HHV-8 is primarily limited to AIDS and KS patients. In countries with high seroprevalence, infection is frequent in childhood, indicating a likely mother-to-child transmission by saliva. In a Zambia
Zambia, officially the Republic of Zambia, is a landlocked country at the crossroads of Central Africa, Central, Southern Africa, Southern and East Africa. It is typically referred to being in South-Central Africa or Southern Africa. It is bor ...
n 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. In another Zambian survey, 13.8% of children were seropositive for HHV-8 by age 4. Seroprevalence has not been shown to vary significantly because of gender or marital status.
Evolution
The most recent common ancestor
A most recent common ancestor (MRCA), also known as a last common ancestor (LCA), is the most recent individual from which all organisms of a set are inferred to have descended. The most recent common ancestor of a higher taxon is generally assu ...
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.[Liu Z, Fang Q, Zuo J, Minhas V, Wood C, He N, Zhang T (2017) Was Kaposi's sarcoma-associated herpesvirus introduced into China via the ancient Silk Road? An evolutionary perspective. Arch Virol] 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
Roman or Romans most often refers to:
*Rome, the capital city of Italy
*Ancient Rome, Roman civilization from 8th century BC to 5th century AD
*Roman people, the people of Roman civilization
*Epistle to the Romans, shortened to Romans, a letter w ...
period it seems likely that this virus was introduced to Xinjiang along the Silk Road
The Silk Road was a network of Asian trade routes active from the second century BCE until the mid-15th century. Spanning over , it played a central role in facilitating economic, cultural, political, and religious interactions between the ...
. The mutation rate was estimated to be substitutions per site per year (95% highest probability density to ). However, the global distribution of different genotypes of KSHV and the potential transmission path need further studies.
Typing of isolates is based on the variable K1 membrane protein. Six types are recognised (A–F).[Jary A, Leducq V, Desire N, Petit H, Palich R, Joly V, Canestri A, Gothland A, Lambert-Niclot S, Surgers L, Amiel C, Descamps D, Spano JP, Katlama C, Calvez V, Marcelin AG (2020) New Kaposi's sarcoma-associated herpesvirus variant in men who have sex with men associated with severe pathologies. J Infect Dis]
Prevention
Since persons infected with KSHV will asymptomatically give the virus, caution should be used by sex partner
Sexual partners are people who engage in sexual activity together. The sexual partners may be in a committed relationship, either on an exclusive basis or not, or engage in the sexual activity on a casual basis. They may be on intimate terms (i ...
s in having unprotected sex
Safe sex is sexual activity using methods or contraceptive devices (such as condoms) to reduce the risk of transmitting or acquiring sexually transmitted infections (STIs), especially HIV. "Safe sex" is also sometimes referred to as safer se ...
and activities where saliva might be shared during sexual activity. Prudent advice is to use condom
A condom is a sheath-shaped Barrier contraception, barrier device used during sexual intercourse to reduce the probability of pregnancy or a Sexually transmitted disease, sexually transmitted infection (STI). There are both external condo ...
s when needed and avoid deep kissing with partners who may have KSHV infections.
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 anthracycline
Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from '' Streptomyces peucetius'' bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, b ...
s or paclitaxel
Paclitaxel, sold under the brand name Taxol among others, is a chemotherapy medication used to treat ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer. It is administered b ...
may be used, particularly for invasive disease. Antiviral drugs, such as ganciclovir
Ganciclovir, sold under the brand name Cytovene among others, is an antiviral medication used to treat cytomegalovirus (CMV) infections.
Ganciclovir was patented in 1980 and approved for medical use in 1988.
Medical use
Ganciclovir is indicated ...
, that target the replication of herpesviruses such as KSHV have been used to successfully prevent development of Kaposi's sarcoma, although once the tumor develops these drugs are of little or no use. For patients with AIDS-KS, the most effective therapy is highly active antiretroviral therapy
The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of mul ...
to reduce HIV infection. AIDS patients receiving adequate anti-HIV treatment may have up to a 90% reduction in Kaposi's sarcoma occurrence.
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 cell death protein 1 (PD-1), (CD279 cluster of differentiation 279). PD-1 is a protein encoded in humans by the ''PDCD1'' gene. PD-1 is a cell surface receptor on T cells and B cells that has a role in regulating the immune system's re ...
)/programmed death-ligand 1 (PD-L1
Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the ''CD274'' gene.
Programmed death-ligand 1 (PD-L1) is a 40kDa type 1 transmembrane prote ...
) 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
Nivolumab, sold under the brand name Opdivo, is an anti-cancer medication in the class of immune checkpoint inhibitors. It selectively binds and blocks the programmed death-1 (PD-1) receptor on T cells, thereby facilitating their activation ...
or pembrolizumab
Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody, more specifically a PD-1 inhibitor, used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cerv ...
), 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
Pomalidomide, sold under the brand names Pomalyst and Imnovid, is an anti-cancer medication used for the treatment of multiple myeloma and AIDS-related Kaposi sarcoma.
Pomalidomide was approved for medical use in the United States in February ...
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.
KSHV genes
KSHV encodes for ~90 genes and multiple non-coding RNAs, such as microRNAs. 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.
ORF2 – dihydrofolate reductase
Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in one-carbon transfer chemistry. ...
ORF8 – gB – envelope glycoprotein
Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
involved in viral entry
ORF9 – Pol8 – DNA polymerase
A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create t ...
required for viral DNA replication
ORF10 – regulates RNA export and responses to type I IFNs
ORF16 – vBcl2
Bcl-2, encoded in humans by the ''BCL2'' gene, is the founding member of the apoptosis regulator proteins, Bcl-2 family, Bcl-2 family of regulator proteins. BCL2 blocks programmed cell death (apoptosis) while other BCL2 family members can eithe ...
ORF18, ORF24, ORF30, ORF31, ORF34, ORF66 – viral transcription factors required for the expression of late genes
ORF21 – vTK – thymidine kinase
Thymidine kinase is an enzyme, a phosphotransferase (a kinase): 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21. It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Cert ...
ORF22 – gH – envelope glycoprotein
Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
involved in viral entry
ORF23 – uncharacterized
ORF25, ORF26 and ORF65 – capsid
A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or m ...
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
Deoxyribonuclease (DNase, for short) refers to a group of glycoprotein endonucleases which are enzymes that catalyze the hydrolytic cleavage of phosphodiester linkages in the DNA backbone, thus degrading DNA. The role of the DNase enzyme in cells ...
activity required for genome packaging and RNase
Ribonuclease (commonly abbreviated RNase) is a type of nuclease that catalyzes the degradation of RNA into smaller components. Ribonucleases can be divided into endoribonucleases and exoribonucleases, and comprise several sub-classes within the ...
activity regulates host gene expression
ORF38 – involved in viral particle formation
ORF39 – gM – envelope glycoprotein
Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
ORF40 and ORF41 – helicase
Helicases are a class of enzymes that are vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic double helix, separating the two hybridized ...
and primase
DNA primase is an enzyme involved in the replication of DNA and is a type of RNA polymerase. Primase catalyzes the synthesis of a short RNA (or DNA in some
living organisms) segment called a primer complementary to a ssDNA (single-stranded ...
– DNA replication
ORF42 – uncharacterized
ORF45 – tegument
Tegument may refer to:
* Integumentary system, a protective organ system forming the outermost layer of an animal's body
* Tegument (helminth), an outer covering characteristic of flatworms
* Viral tegument
A viral tegument or tegument, more ...
protein, binds and prevents dephosphorylation of p90 ribosomal S6 kinases (RSKs) and ERK for modulate the ERK/RSK MAPK
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflamm ...
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
Tegument may refer to:
* Integumentary system, a protective organ system forming the outermost layer of an animal's body
* Tegument (helminth), an outer covering characteristic of flatworms
* Viral tegument
A viral tegument or tegument, more ...
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
Thymidylate synthase (TS) () is an enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thymidine is one of the nucleotides in DNA. With inhibition of TS, an imbalance of deoxynucleot ...
ORF72 – vCyclin
Cyclins are proteins that control the progression of a cell through the cell cycle by activating cyclin-dependent kinases (CDK).
Etymology
Cyclins were originally discovered by R. Timothy Hunt in 1982 while studying the cell cycle of sea urch ...
ORF73 – LANA
Lana may refer to:
*Lana (given name)
*Francesco Lana de Terzi (1631–1687), Italian Jesuit priest and scientist
*Lana Del Rey, American singer-songwriter
*Lana Turner, American actress
*Lana Rhoades, American former adult film actress
* CJ Perr ...
, 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, polyadenylated nuclear RNA
Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...
– non–coding linear and circular RNAs
miRNA
Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcri ...
s (mirKs) – viral microRNAs expressed during latency to regulate proliferation and cell death
K1 – involved in oncogenesis
K2 – Interleukin 6
Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene.
In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smoo ...
homolog,
K3 and K5 – ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...
E3 ligase
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin ...
s – regulates antigen presentation
K4 – vCCL2 – chemokine
Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addit ...
K4.1 – vCCL3 – chemokine
Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addit ...
K8 – transcriptional repressor – modulates chromatin
K8.1 – envelope glycoprotein
Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
K9 – v IRF1, viral interferon regulatory factor
Interferon regulatory factors (IRF) are proteins which regulate transcription of interferons (see regulation of gene expression). Interferon regulatory factors contain a conserved N-terminal region of about 120 amino acids, which folds into a s ...
1
K10 – v IRF4. A circular RNA (circRNA
In molecular biology, circular ribonucleic acid (or circRNA) is a type of single-stranded RNA which, unlike linear RNA, forms a covalently closed continuous loop. In circular RNA, the 3' and 5' ends normally present in an RNA molecule have been ...
) is also generated from this locus
Locus (plural loci) is Latin for "place". It may refer to:
Mathematics and science
* Locus (mathematics), the set of points satisfying a particular condition, often forming a curve
* Root locus analysis, a diagram visualizing the position of r ...
.
K10.5 – v IRF3 (initially designated LANA2), is expressed during latency in PEL cell lines, but is also a bona fide lytic factor, like all of the vIRFs.
K11 – v IRF2
K12 – kaposin
K13 – v FLIP
See also
* Oncovirus
An oncovirus or oncogenic virus is a virus that can cause cancer. This term originated from studies of acutely transforming retroviruses in the 1950–60s, when the term ''oncornaviruses'' was used to denote their RNA virus origin. With the let ...
(cancer virus)
* Smoker's paradox
References
Further reading
*
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
{{DEFAULTSORT:Kaposi's Sarcoma-Associated Herpesvirus
Gammaherpesvirinae
Sexually transmitted diseases and infections
Infectious causes of cancer
IARC Group 1 carcinogens