User:Lawrence2009

Avian Sarcoma and Leukosis Viruses (ASLV)

Avian sarcoma and leukosis virus (ASLV) is a retrovirus that infects and can lead to cancer in chickens. ASLV replicates in chicken embryo fibroblasts, the cells that contribute to the formation of connective tissues.

ASLV can only naturally infect chickens. Experiments have shown, however, that it can infect and produce tumors in other types of fowl, such as quail and pheasants, and even some mammals.

Brief History
Sarcoma in chickens has been studied since the early 1900s when Ellerman and Bang showed 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 [1], [2]. Rous was awarded the Nobel Prize for his discovery in 1966.

By the 1960s, ASLV was becoming a problem with egg-laying hens and effort was made to isolate the disease, however, the movement was unsuccessful in maintaining leukosis-free flocks [1]. 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 for this in 1975 [2].

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 [32]. A detailed understanding of retroviral cell entry may lead to the discovery of ways in which to block the viruses from entering cells. Also, retroviruses have the potential to serve as gene delivery vectors in gene therapy.

Classification
ASLV is a Group VI virus of the family Retroviridae. It is of the Alpharetrovirus genus, and has a C-type morphology. Hence, it is enveloped with a condensed, central core, and has barely visible envelope spikes, or proteins [2].

ASLV is divided into six subgroups, labelled A through E and J, each having a different antigenicity due to variances in viral envelope glycoproteins. Strains A through E are highly related and are believed to have evolved from the same ancestor [20]. The subgroups are believed to have evolved to utilize difference cellular receptors to gain entry into avian cells due to the host developing resistance to viral entry [4]. Some antigenic variation can occur within subgroups, and all strains are oncogenic, but oncogenicity and the ability to replicate varies between subgroups [1].

Viral Structure and Composition
Like all retroviruses, ASLV consists of a lipid envelope with transmembrane and cell surface glycoproteins. Within the envelope is a capsid surrounding single stranded RNA, integrase, 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, and vr3, on the surface glycoproteins. Binding specificity is determined primarily by the hr1 and hr2 regions, with the vr3 region contributing to receptror recognition but not to binding specificity of the viral glycoprotein and cellular receptor [7].

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. The ability for the virus to infect a cell depends on the cell surface receptors for the viral subgroups. [16]. Tva contains sequences related to the ligand binding region of low-density lipoproteins receptors (LDLR) [32]. The Tvb receptor is believed to be very closely related to the receptors for both ASLV D and E and is a member of the tumor necrosis factor receptor (TNFR) family [20]. The Tvc receptor is closely related to mammalian butyrophilins, which are members of the immunoglobulin superfamily [22].

ASLV is closely related to the Rous sarcoma virus (RSV) genetically, 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 [1]. Both, however, 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 transmembrane [32].