Acutely Transforming Avian Leukosis Virus Subgroup J Strain 966: Defective Genome Encodes a 72-Kilodalton Gag-Myc Fusion Protein

Abstract

Avian leukosis virus subgroup J (ALV-J) is the newest member of the avian oncogenic retroviruses. After the first isolation of the ALV-J prototype virus, HPRS-103, more than 10 years ago in the United Kingdom (21), viruses belonging to this subgroup have spread rapidly to many countries, becoming one of the major pathogens facing the broiler meat industry worldwide (26). The env gene of ALV-J is closely related to that of a novel group of chicken endogenous retroviral elements designated EAV-HP (24), suggesting that ALV-J has emerged by genetic recombination (17). Compared to the pathogenic ALV subgroups, such as A and B, which primarily induce lymphoid leukosis in genetically susceptible birds (18), ALV-J isolates predominantly induce myeloid leukosis (ML), a property thought to be associated with their tropism for the cells of the myeloid lineage (1). Previous studies have shown that HPRS-103 and other ALV-J isolates do not transform chicken bone marrow cell cultures in vitro and that the tumors induced by these viruses occur after long latent periods (19). These observations and the demonstration that the nucleotide sequence of the viral genome does not carry any viral oncogenes (2, 3) suggested that ALV-J-induced oncogenesis occurs by the activation of oncogenes through the mechanism of insertional mutagenesis (13).Although the tumors induced by HPRS-103 are of late onset, occurring at a median age of 20 weeks (19), we have previously shown that acutely transforming ALVs that induce rapid-onset tumors could be isolated from about 60% of lateonset tumors (20). Many tumors obtained from field cases of ML also contained acutely transforming viruses, suggesting that generation of acutely transforming ALVs is a common feature of ALV-J-induced oncogenesis. Most of these virus isolates were able to transform chicken bone marrow or monocyte cell cultures in vitro and induce rapid-onset tumors when inoculated into susceptible birds, a property attributed to the transduction of oncogenes. The acutely transforming ALV-J strain 966 was recovered from a myeloid tumor induced experimentally by . This virus transformed peripheral blood monocyte and bone marrow cells and induced rapid-onset tumors in chickens (20) and turkeys (28). Peripheral blood monocytes and bone marrow cells from different lines of chickens showed variation in the relative susceptibility to transformation by ALV-J strain 966 (1). This variation was correlated with the relative susceptibility to the induction of ML by HPRS-103, suggesting the involvement of common cell-specific viral and/or host factors in oncogenesis induced by these two viruses. In order to identify the viral genes and oncogenes that are involved in the rapid induction of tumors, we have determined the complete sequence of the proviral genome of ALV-J strain 966. In this paper, we demonstrate the genome structure of the provirus of the 966 strain of ALV-J and compare its sequence with that of HPRS-103 and other acutely transforming avian retroviruses. We also present data demonstratin...

Human Immunodeficiency Virus Type 1 Transductive Recombination Can Occur Frequently and in Proportion to Polyadenylation Signal Readthrough

“…The spectrum of nonhomologous products was similar to those reported for oncogene-virus 3Ј junctions (11,14,17,23,61) and other retroviral genetic rearrangements, including the occasional transduction of cellular RNA sequences within deletions (32,33,36,57). Note that the donor RNA template contains two copies of the internal portion of the lacZ gene, either of which could serve as a patch repair donor.…”

The MYC , TERT , and ZIC1 Genes Are Common Targets of Viral Integration and Transcriptional Deregulation in Avian Leukosis Virus Subgroup J-Induced Myeloid Leukosis

“…MYC expression is highly regulated, so its deregulated expression is sufficient to drive oncogenesis in some transgenic mouse tissues (43). In particular, the observation of fusion transcript ALV-J Gag-Myc in ALV-J-transformed bone marrow cells demonstrated effective retroviral integration into the regulatory region of MYC, leading to the loss of the first exon and the activation of this oncogene (44). In our study, the ALV-J provirus mostly integrated into the region proximal to the MYC transcription start site (TSS) in the forward transcriptional orientation, where many transcriptional regulatory motifs are located.…”

Identification of avian leukosis virus subgroup J-associated acutely transforming viruses carrying the v-src oncogene in layer chickens

“…A series of td109-derived rASVs containing deletions to the env, pol and gag genes were replaced by various lengths of v-src oncogenes (Wang et al, 1984). A similar event occurred in ALV-J strain 966, which is an ATV carrying the v-myc oncogene isolated from chicken bone marrow infected with HRPS-103 (Chesters et al, 2001). A range of viral genomes with structures similar to that of ALV-J strain 966 was identified by PCR amplification in tumours induced by HRPS-103.…”

“…Consequently, these viruses can only replicate when the replication-competent viruses that function as helper viruses co-exist to provide viral gene products. Most of the isolated ATVs are currently subgroup A/B/C/E-associated replication-defective viruses, with only 966 and Fu-J using ALV-J as their helper virus (Chen et al, 2012;Chesters et al, 2001). Another ATV strain was isolated recently from fibrosarcomas obtained from a 240-day-old ALV-J-infected Hy-Line Brown commercial layer chicken in China.…”

“…However, most ATVs are replication defective and can replicate only when replication-competent viruses are present to serve as 'helper viruses'. There have been few reports of the isolation and identification of ALV-J-associated ATVs; however, it was demonstrated recently that the ATV strain 966 carrying a v-myc oncogene, isolated from an ALV-J-induced tumour, could induce a rapid onset of tumours in chickens (Chesters et al, 2001;Payne et al, 1993).…”