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In sheep infected with bovine leukemia virus (BLV), transcription of structural, enzymatic, and accessory genes is silenced. However, the BLV provirus transcribes a series of non-coding RNAs that remain undetected by the host immune response. Specifically, three RNAs (AS1-L, AS1-S, and AS2) are consistently expressed from the antisense strand, originating from transcriptional initiation at the 3’-Long Terminal Repeat (LTR). To investigate the role of these non-coding RNAs in viral replication and pathogenesis, a reverse genetics approach was devised, capitalizing on a mechanistic disparity in transcription initiation between the 5’ and 3’ promoters. A two-nucleotide mutation (GG>TA) in the TFIIB-recognition element (BRE) impaired antisense transcription originating from the 3’-LTR. In the context of the provirus, this 2bp mutation significantly diminished the expression of antisense RNAs, while not notably affecting sense transcription. When inoculated to sheep, the mutated provirus was infectious but exhibited reduced replication levels, shedding light on the role of antisense transcription in vivo. In comparison to lymphoid organs in sheep infected with a wild-type (WT) provirus, the mutant demonstrated alterations in both the spatial distribution and rates of cell proliferation in the lymph nodes and the spleen. Analysis through RNA sequencing and RT-qPCR unveiled an upregulation of the Hmcn1/ hemicentin-1 gene in B-lymphocytes from sheep infected with the mutated provirus. Further examination via confocal microscopy and immunohistochemistry revealed an increase in the amount of hemicentin-1 protein encoded by Hmcn1 in peripheral blood mononuclear cells (PBMCs) and lymphoid organs of sheep infected with the mutant. RNA interference targeting Hmcn1 expression impacted the migration of ovine kidney (OVK) cells in vitro . In contrast to the WT, the mutated provirus showed reduced oncogenicity when inoculated into sheep. Collectively, this study underscores the essential role of antisense transcription in BLV replication and pathogenicity. These findings may offer valuable insights into understanding the relevance of antisense transcription in the context of human T-cell leukemia virus (HTLV-1).

Bovine leukaemia virus (BLV) is a deltaretrovirus that is closely related to human T-cell leukaemia virus types 1 and 2 (HTLV-1 and -2). It causes enzootic bovine leukosis (EBL), which is the most important neoplastic disease in cattle. Most BLV-infected cattle are asymptomatic, which potentiates extremely high shedding rates of the virus in many cattle populations. Approximately 30% of them show persistent lymphocytosis that has various clinical outcomes; only a small proportion of animals (less than 5%) exhibit signs of EBL. BLV causes major economic losses in the cattle industry, especially in dairy farms. Direct costs are due to a decrease in animal productivity and in cow longevity; indirect costs are caused by restrictions that are placed on the import of animals and animal products from infected areas. Most European regions have implemented an efficient eradication programme, yet BLV prevalence remains high worldwide. Control of the disease is not feasible because there is no effective vaccine against it. Therefore, detection and early diagnosis of the disease are essential in order to diminish its spreading and the economic losses it causes. This review comprises an overview of bovine leukosis, which highlights the epidemiology of the disease, diagnostic tests that are used and effective control strategies.

Bovine leukemia virus (BLV), an oncogenic member of the Deltaretrovirus genus, is closely related to human T-cell leukemia virus (HTLV-I and II). BLV infects cattle worldwide and causes important economic losses. In this review, we provide a summary of available information about commonly used diagnostic approaches for the detection of BLV infection, including both serological and viral genome-based methods. We also outline genotyping methods used for the phylogenetic analysis of BLV, including PCR restriction length polymorphism and modern DNA sequencing-based methods. In addition, detailed epidemiological information on the prevalence of BLV in cattle worldwide is presented. Finally, we summarize the various BLV genotypes identified by the phylogenetic analyses of the whole genome and env gp51 sequences of BLV strains in different countries and discuss the distribution of BLV genotypes worldwide.

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.

Coinfections can alter the adaptive immune responses to bovine tuberculosis (bTB) and hinder accurate diagnosis; however, their effect on host immunity to Mycobacterium bovis and disease progression is not well understood. In this study, we assessed the impact of natural coinfection with bovine leukemia virus (BLV) on immune responses to M. bovis . Among 108 cattle examined, those coinfected with BLV showed a significantly higher intragranulomatous mycobacterial burden and more severe pathological lesions compared to animals infected with M. bovis alone. Additionally, coinfected animals demonstrated a granulomatous response characterized by reduced lymphocyte populations, increased neutrophil infiltration, and diminished granuloma encapsulation, suggesting a compromised antimycobacterial immune response. Supporting this hypothesis, BLV-infected cattle exposed to mycobacterial antigens displayed impaired delayed-type hypersensitivity (type IV hypersensitivity) to a purified protein derivative of M. bovis as well as reduced antibody response. These findings indicate that BLV coinfection influences the immunopathogenesis of bTB, exacerbates disease progression in cattle naturally infected with M. bovis , and may reduce the predictive reliability of diagnostic methods used in bTB control programs.

Bovine leukemia virus (BLV) is the causative agent of enzootic bovine leukosis. It causes significant economic losses associated with losses due to slaughter and eradication of infected animal from infected area and other indirect economic losses such as restriction on importation of animals and semen from infected area. The main objective of this study was to determine the seroprevalence of BLV antibodies in cattle, buffaloes, and camels in Egypt using ELISA test. Serum samples were collected from 350 cattle, 100 buffaloes, and 100 camels during 2018. The seropositivity for BLV-specific antibody was 20.8%, 9%, and 0% in cattle, buffaloes, and camels, respectively. The result revealed significant association (p < 0.05) between age and seroprevalence of BLV infection in cattle > 4 years (24%) compared with those < 4 years (13%). We found no significant association between pregnancy and herd size and seroprevalence of BLV infection in this study (p > 0.05). Furthermore, the age, pregnancy state, and herd size had significant effect on seroprevalence of BLV infection in buffaloes. This study contributes that BLV is detected in cattle and buffaloes in Egypt and confirms that the camels has resistance against BLV infection. Hence, the control measures are very necessary to combat the transmission of the disease and reduce its economic impact.

Bovine leukemia virus (BLV) is a retrovirus that causes leukemia-like disorders in cattle and sheep, as well as inflammatory conditions and reduced milk production in dairy cows, leading to substantial economic losses in the global cattle industry. BLV infection is widely prevalent among cattle populations worldwide. Emerging evidence has indicated a potential association between BLV infection and human breast cancer development. In several regions, BLV DNA has been detected in human breast tissue samples, particularly in tumor cells, suggesting that BLV may contribute to the development of breast cancer. This review summarizes recent advances in research on the possible link between BLV and human breast cancer, emphasizing its potential public health significance. Furthermore, we examine progress in the development of preventive vaccines, which may play a crucial role in mitigating BLV transmission.

To identify a biomarker for the early diagnosis of enzootic bovine leukosis (EBL) caused by bovine leukemia virus (BLV), we investigated the expression of a microRNA, bta-miR-375, in cattle serum. Using quantitative reverse-transcriptase PCR analysis, we measured bta-miR-375 levels in 27 samples from cattle with EBL (EBL cattle), 45 samples from animals infected with BLV but showing no clinical signs (NS cattle), and 30 samples from cattle uninfected with BLV (BLV negative cattle). In this study, we also compared the kinetics of bta-miR-375 with those of the conventional biomarkers of proviral load (PVL), lactate dehydrogenase (LDH), and thymidine kinase (TK) from the no-clinical-sign phase until EBL onset in three BLV-infected Japanese black (JB) cattle. Bta-miR-375 expression was higher in NS cattle than in BLV negative cattle ( P < 0.05) and greater in EBL cattle than in BLV negative and NS cattle ( P < 0.0001 for both comparisons). Receiver operating characteristic curves demonstrated that bta-miR-375 levels distinguished EBL cattle from NS cattle with high sensitivity and specificity. In NS cattle, bta-miR-375 expression was increased as early as at 2 months before EBL onset—earlier than the expression of PVL, TK, or LDH isoenzymes 2 and 3. These results suggest that serum miR-375 is a promising biomarker for the early diagnosis of EBL.

Despite significant advancements in early diagnosis and treatment, breast cancer (BC) remains a major global health challenge. Ongoing research is essential to identify novel risk factors, implement innovative screening programs, and develop personalized treatment approaches. Among the various risk factors, infection with certain oncogenic viruses has emerged as a potential contributor to BC development. Increasing evidence suggests that bovine leukemia virus (BLV) may contribute to zoonotic infections in humans, with a potential role in BC initiation and progression. This review evaluates clinical and experimental data on BLV presence in both malignant and non-malignant breast tissues, exploring potential mechanisms through which BLV may access human breast tissue and contribute to carcinogenesis. Current data reveal a higher prevalence of BLV infection in BC tissues compared to non-tumor tissues, correlating with an increased risk of BC development. In this context, dairy and meat products from BLV-infected animals have been proposed as potential transmission sources. BLV-encoded proteins disrupt key oncogenic pathways, which support their possible role in breast carcinogenesis. However, the interpretation of these findings is limited by potential confounding factors such as genetic predisposition, environmental exposures, and dietary influences. Further research, including well-controlled epidemiological studies, longitudinal cohorts, and mechanistic investigations into BLV proteins in human breast cells, is necessary to determine its role in BC development.

Bovine leukemia virus (BLV) causes enzootic bovine leukosis (EBL), yet its pathogenic mechanisms remain largely unclear. In particular, the role of BLV genomic integration sites (IS(s)) in BLV-induced leukemogenesis has not been fully elucidated. Here, we identified a total of 235 ISs from 99 BLV-infected cattle with lymphoma, of which 4.3% and 46.8% were located within exon and intron, respectively, while no preferential integration into CpG islands or repetitive regions was observed. All identified ISs were distinct, and no identical sites were detected among the samples. We identified 246 genes related with these ISs and protein–protein interaction analysis of these genes demonstrated one “IS-Clustered genes” composed of 85 among 246 genes. This “IS-Clustered genes” contains 12 cancer genes (14.1%) with high significantly proportion. Notably, with 55 among 99 cattle tested (55.6%) harboring ISs within this cluster, suggesting its crucial involvement in BLV-induced pathogenesis. Furthermore, integrated analysis of known lymphoma- and IS-related genes and the 85 “IS-Clustered genes” showed that key genes formed a shared cluster, indicating a potential “common EBL-associated cluster.” These findings provide important insights into the role of BLV integration in EBL development and may contribute to elucidating its molecular mechanisms underlying onset of EBL. In addition, these findings may also aid in the development of therapeutic strategies and facilitate early diagnosis.