Avian Sarcoma Leukosis Virus
Encyclopedia
Avian sarcoma leukosis virus (ASLV) is an endogenous retrovirus
that infects and can lead to cancer in chickens; experimentally it can infect other species of birds and mammals. ASLV replicates in chicken
embryo
fibroblasts, the cells that contribute to the formation of connective tissues. Different forms of the disease exist, including lymphoblast
ic, erythroblastic, and osteopetrotic
.
Avian Sarcoma Leukosis Virus is characterized by a wide range of tumors, the most common of which are lymphoma
s. The disease is also characterized by an enlarged liver
due to infiltration of cancerous lymphoid
cells. In addition, other abdominal organs and the bursa of Fabricius
are often infected.
in chickens has been studied since the early 1900s when Ellerman and Bang demonstrated that erythroleukemia
can be transmitted between chickens by cell-free tissue filtrates, and in 1911 when (Francis) Peyton Rous proved that sarcoma can be transmitted through cell free extracts of solid chicken tumors. Rous was awarded the Nobel Prize
for his discovery in 1966 .
By the 1960s, ASLV became a problem with egg-laying hens and effort was made to isolate the disease. However, the movement was unsuccessful in maintaining leukosis-free flocks. In 1961, Rous sarcoma virus
(RSV), which is closely related to ASLV, was shown to contain RNA, and oncogenic viruses, such as RSV and ASLV, were termed RNA tumor viruses. By the late 1960s, Howard Temin hypothesized that RSV made a copy of its own DNA and integrated that into the host cell’s chromosomal DNA. Much debate in the scientific community surrounded this issue until DNA integration was demonstrated by Temin in 1968 and reverse transcriptase was independently discovered by both Temin and David Baltimore
in 1970. Temin and Baltimore won the Nobel Prize in Medicine in 1975 .
Today, research is carried out on ASLV in order to better understand retroviral cell entry. Since ASLV uses distinct cellular receptors to gain entry into cells, it has proven useful for understanding the early events in retroviral infection . A detailed understanding of retroviral cell entry may lead to the discovery of ways in which to block the viruses from entering cells. Retroviruses also have the potential to serve as gene delivery vectors in gene therapy
.
genus, and has a C-type morphology. Hence, it is an enveloped virus with a condensed, central core, and has barely visible envelope spikes, or proteins .
ASLV is divided into six subgroups, labelled A through E and J, each having a different antigenicity
due to variances in viral envelope
glycoprotein
s. Strains A through E are highly related and are believed to have evolved from the same ancestor. The subgroups evolved to utilize difference cellular receptors to gain entry into avian cells due to the host developing resistance to viral entry . Some antigenic variation can occur within subgroups, and all strains are oncogenic, but oncogenicity and the ability to replicate varies between subgroups .
, protease
, and reverse transcriptase
, an enzyme that allows for the reversal of genetic transcription. As with all retroviruses, the virus is transcribed from RNA to DNA, instead of DNA to RNA as in normal cellular replication.
Viral glycoprotein-receptor interactions are required to initiate membrane fusion of the virus and cell. The surface glycoproteins contain the major domains that interact with the host cell receptor while the transmembrane (TM) glycoproteins anchor the surface glycoproteins to the virus membrane. The TM glycoproteins are directly involved in the fusion of the virus and host membranes for entry. The surface glycoproteins for subgroups A-E are almost identical and include the conservation of all cysteine
amino acid
residues. Viral specificity is determined by five hyper variable regions, vr1, vr2, hr1, hr2, and vr3, on the surface glycoproteins. Binding specificity is determined primarily by the hr1 and hr2 regions, with the vr3 region contributing to receptor recognition but not to binding specificity of the viral glycoprotein and cellular receptor .
In chicken chromosomes, three autosomal loci, t-va, t-vb, and t-vc, have been identified which control cell susceptibility of the ASLV virus subgroups A, B, and C respectively. Each of these genes codes for the cellular receptors Tva, Tvb, and Tvc.. Tva contains sequences related to the ligand binding region of low-density lipoprotein receptors (LDLR) . The Tvb receptor is believed to be very closely related to the receptors for both ASLV D and E, so that the ASLV D and E will bind to Tvb. Tvb is a member of the tumor necrosis factor receptor (TNFR) family . The Tvc receptor is closely related to mammalian butyrophilins, which are members of the immunoglobulin superfamily .
ASLV is genetically closely related to the Rous sarcoma virus (RSV), but unlike RSV, ASLV does not contain the src gene, which codes for a tyrosine kinase, and does not transform the fibroblasts that it infects . Both RSV and ASLV contain the gag gene, which is common to most retroviruses and encodes for the capsid proteins, and the pol gene which encodes for the reverse transcriptase enzyme. ASLV and some RSVs also contain the env gene, which encodes a precursor polyprotein that assembles in the endoplasmic reticulum
. The polyproteins are then transported to the Golgi apparatus, glycosylated and cleaved to produce two glycoproteins: one surface and one transmembrane .
Endogenous retrovirus
Endogenous retroviruses are sequences in the genome thought to be derived from ancient viral infections of germ cells in humans, mammals and other vertebrates; as such their proviruses are passed on to the next generation and now remain in the genome....
that infects and can lead to cancer in chickens; experimentally it can infect other species of birds and mammals. ASLV replicates in chicken
Chicken
The chicken is a domesticated fowl, a subspecies of the Red Junglefowl. As one of the most common and widespread domestic animals, and with a population of more than 24 billion in 2003, there are more chickens in the world than any other species of bird...
embryo
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
fibroblasts, the cells that contribute to the formation of connective tissues. Different forms of the disease exist, including lymphoblast
Lymphoblast
Lymphoblasts are immature cells which typically differentiate to form mature lymphocytes. Normally lymphoblasts are found in the bone marrow, but in acute lymphoblastic leukemia , lymphoblasts proliferate uncontrollably and are found in large numbers in the peripheral blood.The size is between 10...
ic, erythroblastic, and osteopetrotic
Osteopetrosis
Osteopetrosis, literally "stone bone", also known as marble bone disease and Albers-Schonberg disease is an extremely rare inherited disorder whereby the bones harden, becoming denser, in contrast to more prevalent conditions like osteoporosis, in which the bones become less dense and more brittle,...
.
Avian Sarcoma Leukosis Virus is characterized by a wide range of tumors, the most common of which are lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
s. The disease is also characterized by an enlarged liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
due to infiltration of cancerous lymphoid
Lymphoid
Lymphoid is a term used to describe lymph or the lymphatic system.In the context of lymphoid leukemia, it refers specifically to lymphocytes Lymphoid leukemias and lymphomas are now considered to be tumors of the same type of cell lineage. They are called "leukemia" when in the blood or marrow and...
cells. In addition, other abdominal organs and the bursa of Fabricius
Bursa of Fabricius
In birds, the bursa of Fabricius is the site of hematopoiesis, a specialized organ that, as first demonstrated by Bruce Glick and later by Max Cooper and Robert Good, is necessary for B cell development in birds...
are often infected.
History
SarcomaSarcoma
A sarcoma is a cancer that arises from transformed cells in one of a number of tissues that develop from embryonic mesoderm. Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues...
in chickens has been studied since the early 1900s when Ellerman and Bang demonstrated that erythroleukemia
Erythroleukemia
Acute erythroid leukemia is a rare form of acute myeloid leukemia where the myeloproliferation is of erythroblastic precursors.It is defined at type "M6" under the FAB classification.-Types:...
can be transmitted between chickens by cell-free tissue filtrates, and in 1911 when (Francis) Peyton Rous proved that sarcoma can be transmitted through cell free extracts of solid chicken tumors. Rous was awarded the Nobel Prize
Nobel Prize
The Nobel Prizes are annual international awards bestowed by Scandinavian committees in recognition of cultural and scientific advances. The will of the Swedish chemist Alfred Nobel, the inventor of dynamite, established the prizes in 1895...
for his discovery in 1966 .
By the 1960s, ASLV became a problem with egg-laying hens and effort was made to isolate the disease. However, the movement was unsuccessful in maintaining leukosis-free flocks. In 1961, Rous sarcoma virus
Rous sarcoma virus
Rous sarcoma virus is a retrovirus and is the first oncovirus to have been described: it causes sarcoma in chickens.As with all retroviruses, it reverse transcribes its RNA genome into cDNA before integration into the host DNA.-History:...
(RSV), which is closely related to ASLV, was shown to contain RNA, and oncogenic viruses, such as RSV and ASLV, were termed RNA tumor viruses. By the late 1960s, Howard Temin hypothesized that RSV made a copy of its own DNA and integrated that into the host cell’s chromosomal DNA. Much debate in the scientific community surrounded this issue until DNA integration was demonstrated by Temin in 1968 and reverse transcriptase was independently discovered by both Temin and David Baltimore
David Baltimore
David Baltimore is an American biologist, university administrator, and Nobel laureate in Physiology or Medicine. He served as president of the California Institute of Technology from 1997 to 2006, and is currently the Robert A. Millikan Professor of Biology at Caltech...
in 1970. Temin and Baltimore won the Nobel Prize in Medicine in 1975 .
Today, research is carried out on ASLV in order to better understand retroviral cell entry. Since ASLV uses distinct cellular receptors to gain entry into cells, it has proven useful for understanding the early events in retroviral infection . A detailed understanding of retroviral cell entry may lead to the discovery of ways in which to block the viruses from entering cells. Retroviruses also have the potential to serve as gene delivery vectors in gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
.
Classification
ASLV is a Group VI virus of the family Retroviridae. It is of the AlpharetrovirusAlpharetrovirus
Alpharetrovirus is a genus of the retroviridae family. It has type C morphology. Members can cause sarcomas, other tumors, and anaemia of wild and domestic birds and also affect rats....
genus, and has a C-type morphology. Hence, it is an enveloped virus with a condensed, central core, and has barely visible envelope spikes, or proteins .
ASLV is divided into six subgroups, labelled A through E and J, each having a different antigenicity
Antigenicity
Antigenicity is the ability of a chemical structure to bind specifically with certain products of adaptive immunity: T cell receptors or Antibodies . Antigenicity was more commonly used in the past to refer to what is now known as immunogenicity, and the two are still often used interchangeably...
due to variances in viral envelope
Viral envelope
Many viruses have viral envelopes covering their protein capsids. The envelopes typically are derived from portions of the host cell membranes , but include some viral glycoproteins. Functionally, viral envelopes are used to help viruses enter host cells...
glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
s. Strains A through E are highly related and are believed to have evolved from the same ancestor. The subgroups evolved to utilize difference cellular receptors to gain entry into avian cells due to the host developing resistance to viral entry . Some antigenic variation can occur within subgroups, and all strains are oncogenic, but oncogenicity and the ability to replicate varies between subgroups .
Viral structure and composition
Like many retroviruses, ASLV consists of a lipid envelope containing transmembrane and cell surface glycoproteins. Enclosed within the envelope is a capsid surrounding single stranded RNA, integraseIntegrase
Retroviral integrase is an enzyme produced by a retrovirus that enables its genetic material to be integrated into the DNA of the infected cell...
, protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
, and reverse transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
, an enzyme that allows for the reversal of genetic transcription. As with all retroviruses, the virus is transcribed from RNA to DNA, instead of DNA to RNA as in normal cellular replication.
Viral glycoprotein-receptor interactions are required to initiate membrane fusion of the virus and cell. The surface glycoproteins contain the major domains that interact with the host cell receptor while the transmembrane (TM) glycoproteins anchor the surface glycoproteins to the virus membrane. The TM glycoproteins are directly involved in the fusion of the virus and host membranes for entry. The surface glycoproteins for subgroups A-E are almost identical and include the conservation of all cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues. Viral specificity is determined by five hyper variable regions, vr1, vr2, hr1, hr2, and vr3, on the surface glycoproteins. Binding specificity is determined primarily by the hr1 and hr2 regions, with the vr3 region contributing to receptor recognition but not to binding specificity of the viral glycoprotein and cellular receptor .
In chicken chromosomes, three autosomal loci, t-va, t-vb, and t-vc, have been identified which control cell susceptibility of the ASLV virus subgroups A, B, and C respectively. Each of these genes codes for the cellular receptors Tva, Tvb, and Tvc.. Tva contains sequences related to the ligand binding region of low-density lipoprotein receptors (LDLR) . The Tvb receptor is believed to be very closely related to the receptors for both ASLV D and E, so that the ASLV D and E will bind to Tvb. Tvb is a member of the tumor necrosis factor receptor (TNFR) family . The Tvc receptor is closely related to mammalian butyrophilins, which are members of the immunoglobulin superfamily .
ASLV is genetically closely related to the Rous sarcoma virus (RSV), but unlike RSV, ASLV does not contain the src gene, which codes for a tyrosine kinase, and does not transform the fibroblasts that it infects . Both RSV and ASLV contain the gag gene, which is common to most retroviruses and encodes for the capsid proteins, and the pol gene which encodes for the reverse transcriptase enzyme. ASLV and some RSVs also contain the env gene, which encodes a precursor polyprotein that assembles in the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
. The polyproteins are then transported to the Golgi apparatus, glycosylated and cleaved to produce two glycoproteins: one surface and one transmembrane .