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Bovine leukemia virus (BLV) is the causative agent of enzootic bovine leukosis (EBL), of which annual number has rapidly increased in Japan, and it can be divided into two categories based on the amino acid at position 233 in the Tax protein. Here, we conducted a nationwide surveillance of Japanese Black cattle between 2008 and 2021 in Japan. Among 237 tumor samples, 131 (55.3%) and 101 (42.6%) were harbored L233- and P233-Tax, respectively. Onset of EBL under the age of 3 years by L233-Tax-carrying BLV was frequently observed, especially in the animals born via embryo transfer. We also found that L233-Tax-carrying BLV was more prevalent in dairy areas than non-dairy areas. These findings give insight into prevention of EBL.

Bovine leukemia virus (BLV) is the causative agent of enzootic bovine leukosis (EBL) and can be classified into two types based on the amino acid at position 233 in Tax protein, which probably plays crucial roles in leukemogenesis. We previously revealed that L233-Tax-expressing cells secreted chemoattractants for endothelial cells and formed significantly larger tumors accompanying neovascularization than P233-Tax-expressing cells in athymic mice. In the present study, comparative proteomic analysis of the culture medium of Tax-expressing cells revealed that annexin A3 and probably extracellular matrix protein 1 served as chemoattractants. Conversely, L233-Tax-expressing cells were impaired in the secretion of collagen alpha-1 (I) chain precursor, which participates in tissue tension homeostasis, leading to tumor mass development. The analysis also demonstrated that both L233-Tax- and P233-Tax-expressing cells had deficits in the secretion of potentially antiangiogenic molecules, including pigment epithelium-derived factor and collagen alpha-1 (VIII) chain, and they produced complement component 3, which might participate in tumor cell proliferation, metastasis, and immune evasion. These findings provided novel insights into prognostication of EBL and the function of Tax in leukemogenesis induced by BLV., (Copyright © 2021. Published by Elsevier B.V.)

Bovine leukemia virus (BLV) is the causative agent of enzootic bovine leucosis. However, less than 5% of BLV-infected cattle will develop lymphoma, suggesting that, in addition to viral infection, host genetic polymorphisms might play a role in disease susceptibility. Bovine leukocyte antigen (BoLA) -DRB3 is a highly polymorphic gene associated with BLV proviral load (PVL) susceptibility. Due to the fact that PVL is positively associated with disease progression, it is believed that controlling PVL can prevent lymphoma development. Thus, many studies have focused on the relationship between PVL and BoLA-DRB3 . Despite this, there is little information regarding the relationship between lymphoma and BoLA-DRB3 . Furthermore, whether or not PVL-associated BoLA-DRB3 is linked to lymphoma-associated BoLA-DRB3 has not been clarified. Here, we investigated whether or not lymphoma-associated BoLA-DRB3 is correlated with PVL-associated BoLA-DRB3 . We demonstrate that two BoLA-DRB3 alleles were specifically associated with lymphoma resistance ( *010:01 and *011:01 ), but no lymphoma-specific susceptibility alleles were found; furthermore, two other alleles, *002:01 and *012:01 , were associated with PVL resistance and susceptibility, respectively. In contrast, lymphoma and PVL shared two resistance-associated ( DRB3*014:01:01 and * 009:02 ) BoLA-DRB3 alleles. Interestingly, we found that PVL associated alleles, but not lymphoma associated alleles, are related with the anti-BLV gp51 antibody production level in cows. Overall, our study is the first to demonstrate that the BoLA-DRB3 polymorphism confers differential susceptibility to BLV-induced lymphoma and PVL.

Bovine leukemia virus (BLV) can be divided into two categories based on the amino acid at position 233 in the Tax protein, which probably plays a crucial role in leukemogenesis. We show here that a rat fibroblast cell line stably expressing L233-Tax formed significantly larger tumors than P233-Tax-expressing cells in a murine xenograft study. Although the microvessel density was comparable in both tumors, visible blood vessel invasion was observed only on tumors from L233-Tax-expressing cells. Endothelial cell tube formation assays using human umbilical vein endothelial cells showed no significant difference in angiogenic activity between conditioned medium from L233- and P233-Tax-expressing cells, whereas in vitro chemotaxis assays revealed that only L233-Tax-expressing cells produced a chemoattractant for endothelial cells. Since pathological neovascularization can occur from the recruitment of endothelial progenitor cells, these results suggest that L233-Tax-expressing cells recruit murine endothelial progenitor cells and promote neovascularization to support tumor growth. BLV-infected lymphoma cells may also recruit bovine endothelial progenitor cells to promote neovascularization. The findings of this study are consistent with our previous observation that BLV carrying P233-Tax has a significantly longer incubation period for developing tumors than the virus carrying L233-Tax and provide insight into the function of Tax in leukemogenesis by BLV.

Bovine leukemia virus (BLV) is the causative agent of enzootic bovine leucosis (EBL), to which animals are most susceptible at 4-8 years of age. In this study, we examined tumor cells associated with EBL in an 18-year-old cow to reveal that the cells carried at least two different copies of the virus, one of which was predicted to encode a reverse transcriptase (RT) lacking ribonuclease H activity and no integrase. Such a deficient enzyme may exhibit a dominant negative effect on the wild-type RT and cause insufficient viral replication, resulting in delayed tumor development in this cow.

The bovine leukemia virus (BLV) Tax protein is believed to play a crucial role in leukemogenesis by the virus. BLV usually causes asymptomatic infections in cattle, but only one-third develop persistent lymphocytosis that rarely progress after a long incubation period to lymphoid tumors, namely enzootic bovine leucosis (EBL). In the present study, we demonstrated that the BLV tax genes could be divided into two alleles and developed multiplex PCR detecting an L233P mutation of the Tax protein. Then, in order to define the relationship between the Tax protein and leukemogenicity, we examined 360 tumor samples randomly collected from dairy or breeding cattle in Japan, of which Tax proteins were categorized, for age at the time of diagnosis of EBL. The ages of 288 animals (80.0%) associated with L233-Tax and those of 70 animals (19.4%) with P233-Tax individually followed log-normal distributions. Only the two earliest cases (0.6%) with L233-Tax disobeyed the log-normal distribution. These findings suggest that the animals affected by EBL were infected with the virus at a particular point in life, probably less than a few months after birth. Median age of those with P233-Tax was 22 months older than that with L233-Tax and geometric means exhibited a significant difference (P<0.01). It is also quite unlikely that viruses carrying the particular Tax protein infect older cattle. Here, we conclude that BLV could be divided into two categories on the basis of amino acid at position 233 of the Tax protein, which strongly correlated with leukemogenicity., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Bovine leukemia virus (BLV) infection in cattle causes persistent lymphocytosis, and a few percent of infected animals develop lymphoid tumors, namely enzootic bovine leukosis (EBL). In this study, a 440-bp fragment of the env gene was amplified from 204 tumor samples collected from different regions of Japan and analyzed by restriction fragment length polymorphism (RFLP) to determine the association of BLV with EBL. Of the seven RFLP types defined, types I, II, and III were dominant and found in 12.7, 75.0, and 8.3% of tumor samples, respectively. Cattle harboring type III virus were significantly older than other animals at the time of diagnosis of EBL. Type III viruses were found in approximately 33% and 5.5% of Japanese Black and Holstein cattle, respectively, with EBL. These findings indicate that genetically distinct BLV was associated with EBL in Japan and that the genetic profile may influence the leukemogenicity of the virus.

Bovine leukemia virus (BLV) infection of cattle has been increasing yearly in Japan although several European countries have successfully eradicated the infection. In the present study, phylogenetic analysis on the env gene obtained from 64 tumor samples found in different regions in Japan was carried out in order to define the genetic background of BLV strains prevailing in the country. Most of the Japanese isolates were found to reside in the consensus cluster or genotype 1 of BLV strains (Rodriguez et al., 2009). Out of them, 21 isolates and 10 isolates exhibited the identical sequences, respectively. Only one isolate was classified into the different genotype related to the US isolates. Analysis on the deduced amino acids of gp51 demonstrated the sequence diversity in the neutralizing domain. These data may indicate that two major populations of BLV prevailed throughout Japan, whereas antigenic variants also exist. It was further proved that multiple invasion of the genetically different BLV strains have occurred in Japan., (Copyright © 2010 Elsevier B.V. All rights reserved.)