Different animal models have been proposed to investigate the mechanisms of Human T-lymphotropic Virus (HTLV)-induced pathogenesis: rats, transgenic and NOD-SCID/γcnull (NOG) mice, rabbits, squirrel monkeys, baboons and macaques. These systems indeed provide useful information but have intrinsic limitations such as lack of disease relevance, species specificity or inadequate immune response. Another strategy based on a comparative virology approach is to characterize a related pathogen and to speculate on possible shared mechanisms. In this perspective, bovine leukemia virus (BLV), another member of the deltaretrovirus genus, is evolutionary related to HTLV-1. BLV induces lymphoproliferative disorders in ruminants providing useful information on the mechanisms of viral persistence, genetic determinants of pathogenesis and potential novel therapies.

Viruses have coevolved with their host to ensure efficient replication and transmission without inducing excessive pathogenicity that would indirectly impair their persistence. This is exemplified by the bovine leukemia virus (BLV) system in which lymphoproliferative disorders develop in ruminants after latency periods of several years. In principle, the equilibrium reached between the virus and its host could be disrupted by emergence of more pathogenic strains. Intriguingly but fortunately, such a hyperpathogenic BLV strain was never observed in the field or designed in vitro. In this study, we sought to understand the role of envelope N-linked glycosylation with the hypothesis that this posttranslational modification could either favor BLV infection by allowing viral entry or allow immune escape by using glycans as a shield. Using reverse genetics of an infectious molecular provirus, we identified a N-linked envelope glycosylation site (N230) that limits viral replication and pathogenicity. Indeed, mutation N230E unexpectedly leads to enhanced fusogenicity and protein stability. There is no satisfactory treatment for HAM/TSP, and the prognosis for ATLL is still poor despite improved therapies (2). BLV is responsible for major economic losses in cattle due to export limitations, carcass condemnations, and reduction in milk production. BLV infection also correlates with a significant morbidity resulting from opportunistic infections and a decrease in longevity due to tumor development (3). In a proportion (i.e., about one third) of infected cattle, BLV induces a lymphoproliferative disease called persistent lymphocytosis. After a latency period of several years, BLV infection also leads to leukemia and/or lymphoma in a minority (5%) of the infected animals. However, the majority of BLV carriers remain clinically healthy and acts as asymptomatic carriers for viral spread (4). Besides its natural hosts (i.e., cattle, zebu, and water buffalo), BLV can be experimentally transmitted to sheep and goats, where leukemia/lymphoma develops after shorter latency periods (5-7).Retroviral envelope glycoproteins play an important role in the viral life cycle: they contain the recognition site required for entry and mediate cell fusion (8). The BLV envelope is composed of two glycoproteins: a surface (SU) protein, Gp51, and a transmembrane (TM) protein, Gp30, derived from the proteolytic cleavage of a common precursor (gpr72) encoded by the env gene (9-11). The SU protein is N-glycosylated in the rough endoplasmic reticulum by covalent attachment of oligosaccharide chains (12). Although the role of BLV SU-linked glycans is currently unknown, it is expected that N-glycosylation is required for protein folding, stability, or solubility (13). Furthermore, N-glycans are also likely involved in transport of BLV envelope proteins to the cell membrane, binding to cellular receptors and cell-to-cell fusion (14-18) similarly to glycans of the human immunodeficiency virus (HIV) envelope glycoprotein that modulate fusogenicity ...

Viruses have developed different strategies to escape from immune response. Among these, viral non-coding RNAs are invisible to the immune system and may affect the fate of the host cell. Bovine leukemia virus (BLV) encodes both short (miRNAs) and long (antisense AS1 and AS2) non-coding RNAs. To elucidate the mechanisms associated with BLV noncoding RNAs, we performed phenotypic and transcriptomic analyzes in a reverse genetics system. RNA sequencing of B-lymphocytes revealed that cell proliferation is the most significant mechanism associated with ablation of the viral non-coding RNAs. To assess the biological relevance of this observation, we determined the cell kinetic parameters in vivo using intravenous injection of BrdU and CFSE. Fitting the data to a mathematical model provided the rates of cell proliferation and death. Our data show that deletion of miRNAs correlates with reduced proliferation of the infected cell and lack of pathogenesis.