Kaposi's sarcoma-associated herpesvirus
Encyclopedia
Oncovirus
An oncovirus is a virus that can cause cancer. This term originated from studies of acutely-transforming retroviruses in the 1950–60s, often called oncornaviruses to denote their RNA virus origin. It now refers to any virus with a DNA or RNA genome causing cancer and is synonymous with "tumor...
es. It is also the eighth human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses (ITCV) is HHV-8. Like other herpesviruses, its informal name (KSHV) is used interchangeably with its ITCV name. This virus causes Kaposi's sarcoma
Kaposi's sarcoma
Kaposi's sarcoma is a tumor caused by Human herpesvirus 8 , also known as Kaposi's sarcoma-associated herpesvirus . It was originally described by Moritz Kaposi , a Hungarian dermatologist practicing at the University of Vienna in 1872. It became more widely known as one of the AIDS defining...
, a cancer commonly occurring in AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
patients, as well as primary effusion lymphoma
Primary effusion lymphoma
-Causes:It is caused by Kaposi's sarcoma-associated herpesvirus , also known as human herpesvirus 8 .In most cases, the lymphoma cells are also infected with Epstein Barr virus ....
and some types of multicentric Castleman's disease
Castleman's disease
Castleman's disease is an uncommon lymphoproliferative disorder that can involve single lymph node stations or...
.
History
In 1872, Moritz Kaposi described a blood vessel tumor (originally called "idiopathic multiple pigmented sarcoma of the skin") that has since been eponymously named Kaposi's sarcomaKaposi's sarcoma
Kaposi's sarcoma is a tumor caused by Human herpesvirus 8 , also known as Kaposi's sarcoma-associated herpesvirus . It was originally described by Moritz Kaposi , a Hungarian dermatologist practicing at the University of Vienna in 1872. It became more widely known as one of the AIDS defining...
(KS). KS was thought to be an uncommon tumor of Jewish and Mediterranean populations until it was realized that it is actually quite common throughout sub-Saharan Africa. This led to the first suggestions in the 1950s that this tumor might be caused by a virus. With the onset of the AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
epidemic in the early 1980s, there was a sudden epidemic resurgence of KS affecting primarily gay and bisexual 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, led these investigators to propose that KS is caused by an unknown sexually transmitted virus that rarely causes tumors unless the host becomes immunosuppressed, as in AIDS.
It was first found by Yuan Chang
Yuan Chang
Yuan Chang is an American virologist and pathologist who co-discovered Kaposi's sarcoma-associated herpesvirus and Merkel cell polyomavirus, two of the seven known human cancer viruses....
and Patrick S. Moore
Patrick S. Moore
Patrick S. Moore is an American virologist and epidemiologist who co-discovered together with his wife, Yuan Chang, two different human viruses causing the AIDS-related cancer Kaposi's sarcoma and the skin cancer Merkel cell carcinoma...
, a wife and husband team at Columbia University in 1994,http://www.ncbi.nlm.nih.gov/pubmed/7997879 by isolating DNA fragments of a herpesvirus from a Kaposi's sarcoma
Kaposi's sarcoma
Kaposi's sarcoma is a tumor caused by Human herpesvirus 8 , also known as Kaposi's sarcoma-associated herpesvirus . It was originally described by Moritz Kaposi , a Hungarian dermatologist practicing at the University of Vienna in 1872. It became more widely known as one of the AIDS defining...
Cytomegalovirus
Cytomegalovirus is a viral genus of the viral group known as Herpesviridae or herpesviruses. It is typically abbreviated as CMV: The species that infects humans is commonly known as human CMV or human herpesvirus-5 , and is the most studied of all cytomegaloviruses...
and HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
itself. Chang and Moore used representational difference analysis
Representational Difference Analysis
Representational Difference Analysis is a technique used in biological research to find sequence differences in two genomic or cDNA samples. Genomes or cDNA sequences from two samples are PCR amplified and differences analyzed using subtractive DNA hybridization...
, 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 to but distinct from 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 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 Israel, Saudi Arabia, Italy and Greece) and low levels of infection occur in most Northern European and North American populations. Gay and bi-sexual men are more susceptible to infection (through still unknown routes of sexual transmission) whereas the virus is transmitted through non-sexual routes in developing countries.
Virology
KSHV is a herpesvirus, and is a large double-stranded DNA virus with a protein covering that packages its nucleic acids, called the capsidCapsid
A capsid is the protein shell of a virus. It consists of several oligomeric structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The capsid encloses the genetic...
, which is then surrounded by an amorphous protein layer called the tegument
Viral tegument
A viral tegument or tegument, more commonly known as a viral matrix, is a cluster of proteins that lines the space between the envelope and nucleocapsid of all herpesviruses. The tegument generally contains proteins that aid in viral DNA replication and evasion of the immune response, typically...
, and finally enclosed in a lipid envelope derived in part from the cell membrane. KSHV has a genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
which is approximately 165,000 nucleic acid bases in length. It is a rhadinovirus
Rhadinovirus
Rhadinoviruses are a genus of herpesviruses that include the Human herpesvirus 8 , also known as Kaposi's sarcoma-associated herpesvirus , which causes Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. Other names for the Rhadinovirus genus include Rhadinoviridae...
, and is remarkable since it has stolen numerous genes from host cells including genes that encode for complement
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
-binding protein, IL-6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
, BCL-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
, cyclin
Cyclin
Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase enzymes.- Function :...
-D, a G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
, interferon regulatory factor and Flice inhibitory protein (FLIP
Flip
Flip may refer to:* Flip * Flip , a 1985 solo album from Nils Lofgren* Flip , a mathematical operation in algebraic geometry* Flip * Flip , a hinged form factor for handheld electronic devices...
), as well as DNA synthesis proteins including dihydrofolate reductase
Dihydrofolate reductase
- Function :Dihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids...
, thymidine kinase
Thymidine kinase
Thymidine kinase is an enzyme, a phosphotransferase : 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, . It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2...
, thymidylate synthetase, DNA polymerase
Polymerase
A polymerase is an enzyme whose central function is associated with polymers of nucleic acids such as RNA and DNA.The primary function of a polymerase is the polymerization of new DNA or RNA against an existing DNA or RNA template in the processes of replication and transcription...
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.
After infection, the virus enters into lymphocytes where it remains in a latent ("quiet") state expressing the viral latency-associated nuclear antigen, LANA
LANA
The latency-associated nuclear antigen or LANA-1, is a Kaposi's sarcoma-associated herpesvirus latent protein which has been suspected of playing a crucial role in modulating viral and cellular gene expression.. LANA was found by Moore and colleagues as a speckled nuclear antigen present in...
. The virus exists as a naked circular piece of DNA called an episome and uses the cellular replication machinery to replicate itself. LANA tethers the viral DNA to cellular chromosomes, inhibits p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
and retinoblastoma protein
Retinoblastoma protein
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in the majority types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide...
and suppresses viral genes needed for full virus production and assembly ("lytic replication"). Various signals such as inflammation may provoke the virus to enter into lytic replication. When this occurs, the viral episome starts replicating itself in the form of linear DNA molecules that are packaged into virus particles which are expelled from the cell, to infect new cells or to be transmitted to a new host. 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, hence the term lytic replication.
The viral genome consists of a ~145 kbase long unique region, encoding all of expressed viral genes, which is flanked by ~20-30 kbases 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. During latency, the virus genome depends on the host replication machinery and replicates as closed circular episome ("plasmid") using sequences within the terminal repeats as a replication origin. When the virus reactivates into lytic replication, it is believed that the virus genome is replicated as a continuous linear molecule off from 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. 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 recircularizes through a poorly understood process that appears to involve homologous recombination
Homologous recombination
Homologous recombination is a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA. It is most widely used by cells to accurately repair harmful breaks that occur on both strands of DNA, known as double-strand breaks...
.
The primary viral protein responsible for the switch between latent and lytic replication is 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.
Epidemiology
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 immunosuppressed. Cancer patients receiving chemotherapy, AIDS patients and organ transplant patients are all at a high risk of showing signs of infection.Infection with this virus is thought to be life-long, 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. Since persons infected with KSHV will asymptomatically shed the virus, caution should be used by sex partners in having unprotected sex and activities where saliva might be shared during sexual activity. Avoiding deep-kissing (i.e. tonguing the back of a partner's pharynx) and use of saliva as a sexual lubricant is prudent. Blood tests to detect infection exist, but they are largely restricted to research universities, since biomedical companies have not found it economical to develop these tests.
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 anthracyclines or paclitaxel may be used, particularly for invasive disease. Antiviral drugs, such as ganciclovirGanciclovir
Ganciclovir INN is an antiviral medication used to treat or prevent cytomegalovirus infections.Ganciclovir sodium is marketed under the trade names Cytovene and Cymevene . Ganciclovir for ocular use is marketed under the trade name Vitrasert...
, 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
Antiretroviral drug
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART...
to reduce HIV infection. AIDS patients receiving adequate anti-HIV treatment may have up to a 90% reduction in Kaposi's sarcoma occurrence.
External links
- Human Herpesvirus-8: Related Resources HIV InSite
- ucsf.edu Image of KSHV episome, latency genes in green.
