BLV is a single-stranded RNA-RT virus that exhibits a spherical or rod-shaped morphology, measuring approximately 60 to 125 nanometers in diameter. It is enveloped by a double-layered membrane structure and its nucleocapsid demonstrates icosahedral symmetry [32,33]. It contains a diploid single-stranded RNA genome. The viral genome of BLV consists of a diploid single-stranded RNA molecule spanning a total of 8714 nucleotides. This genome encompasses structural protein genes, enzyme coding genes, the pX region, and two identical, long, terminal repeat sequences positioned at both ends of the genome (Figure 1) [34,35].

Structural proteins and enzyme coding genes, such as gag, pro, pol, and env, are crucial in the virus lifecycle, infectivity, and the production of infectious viral particles [36,37,38]. The gag gene is highly conserved and responsible for encoding three major non-glycosylated proteins: p12 nucleocapsid protein (which binds with viral genomic RNA), p15 matrix protein (which binds with viral genomic RNA and interacts with the lipid bilayer of the viral membrane), and p24 nucleocapsid protein (which serves as the main target of the host immune response) [37]. The pro gene encodes the viral proteinase p14, which is involved in the post-translation maturation of the virus [36]. The pol gene encodes reverse transcriptase and integrase, which play a role in the reverse transcription process and integration of proviral BLV DNA into the host genome [39]. The env gene encodes two glycosylated proteins: envelope protein gp51 and transmembrane protein gp30, which facilitate virus–cell fusion through interaction with cell membrane receptors [40,41]. The pX region, located between the env gene and 3’LTR, encodes other auxiliary regulatory or non-structural genes, including regulatory proteins Tax and Rex, as well as auxiliary proteins R3 and G4 [42,43,44,45,46,47,48]. Regulatory proteins are important in virus transcription regulation, inducing the malignant transformation of tumors and virus infection output, while R3 and G4 auxiliary proteins help maintain a high viral load [49]. The env gene also shows genetic polymorphism, which is beneficial for phylogenetic studies and classifying BLV isolates [40]. The nucleotide sequence and amino acid composition of the env gene are valuable genomic markers for studying the distribution of BLV and identifying different genotypes based on geographical origin [50]. Researchers have identified 10 BLV genotypes through sequencing and phylogenetic analysis of partial and full-length gp51 env genes. Genotype 1 is the most prevalent and commonly found in the United States, Japan, and South Korea [51,52,53]. South America has genotypes 1, 2, 3, 4, 5, 6, and 9 (with genotype 9 being particularly prevalent in Bolivia). Russia and Eastern Europe commonly have genotypes 4, 7, and 8 [54]. Genotype 10 is prevalent in China, Vietnam, Thailand, and Myanmar [51,55]. Genotype 4 is found in various countries in North and South America, Africa, and Asia [56,57]. Genotype 6 has been found in South American countries such as Argentina, Brazil, Peru, Paraguay, and Bolivia, as well as in Asian countries such as the Philippines, Thailand, and India [56,58,59,60]. Additionally, genotype 1 has been reported in Egypt [61]. Monitoring the emergence of new viral mutations in veterinary medicine and animal husbandry is important since each new genotype may exhibit unique characteristics in its interaction with the host organism and leukemogenesis is influenced by specific genotypes (Figure 2).

Research indicates that 10 different microRNA (miRNA) can be transcribed under the control of RNA polymerase III in the genomic region spanning from the env gene to the R3 coding area [63]. RNA sequencing analysis has revealed that these miRNAs are highly expressed in primary sheep and cattle cells containing pre-leukemic and malignant B cells, accounting for 40% of the total cellular miRNA [64]. Additionally, elevated levels of BLV miRNA were found in the serum of infected animals, suggesting a potential paracrine role. These findings indicate the important role of BLV miRNAs in the retroviral cycle and/or disease progression, challenging the traditional belief that RNA viruses do not encode miRNAs. They also demonstrate that BLV miRNAs regulate various biological processes, including apoptosis, immunity, signal transduction, and tumorigenesis [65]. Notably, Blv-miR-B4-3p, which shares a seed sequence with the host miRNA miR-29a, is known for downregulating the tumor suppressor genes HMG-box transcription factor 1 (HBP1) and peroxidasin homologs (PXDN) in B-cell tumors [63,65,66]. In vitro studies have confirmed that blv-miR-B4-3p can directly downregulate these genes, although this has not been experimentally validated in cattle infected with BLV. Recently, Petersen et al. used RT-qPCR to analyze hbp1 and pxdn expression in cattle naturally infected with BLV and noted a significant downregulation of pxdn compared to uninfected animals [67]. However, a comprehensive analysis of targets for each mature BLV miRNA is still needed to fully understand the role of BLV in tumorigenesis.