Mechanisms of pathogenesis induced by bovine leukemia virus as a model for human T-cell leukemia virus

Abstract

Bovine leukemia virus (BLV) and human T-cell leukemia virus type 1 (HTLV-1) make up a unique retrovirus family. Both viruses induce chronic lymphoproliferative diseases with BLV affecting the B-cell lineage and HTLV-1 affecting the T-cell lineage. The pathologies of BLV- and HTLV-induced infections are notably similar, with an absence of chronic viraemia and a long latency period. These viruses encode at least two regulatory proteins, namely, Tax and Rex, in the pX region located between the env gene and the 3' long terminal repeat. The Tax protein is a key contributor to the oncogenic potential of the virus, and is also the key protein involved in viral replication. However, BLV infection is not sufficient for leukemogenesis, and additional events such as gene mutations must take place. In this review, we first summarize the similarities between the two viruses in terms of genomic organization, virology, and pathology. We then describe the current knowledge of the BLV model, which may also be relevant for the understanding of leukemogenesis caused by HTLV-1. In addition, we address our improved understanding of Tax functions through the newly identified BLV Tax mutants, which have a substitution between amino acids 240 and 265.

Keywords: B-cell lymphoma; BLV; EBL; HTLV-1; Tax; apoptosis; leukemogensis; transactivation.

FIGURE 1

Schematic representation of genome organization of retroviruses. HTLV-1 and BLV encode unique regulatory and accessory proteins in the pX region. RSV, Rous sarcoma virus; MuLV, murine leukemia virus.

FIGURE 2

BLV-induced leukemogenesis is a multistep process. (A) An infection with BLV is characterized by three progressive stages of disease: asymptomatic stage, persistent lymphocytosis (PL), and lymphoma. BLV infects to cells non-specifically. Among them, BLV Tax protein immortalizes a part of BLV-infected cells, probably only CD5⁺ IgM⁺ B-cells, and induces polyclonal proliferation of the cells. However, the Tax protein does not have the ability to transform the cells. For lymphoma to develop, a malignant transformation needs to occur with the help of host factors, such as p53 mutation, TNF-α activities or bovine leukocyte antigen (BoLA) class II phosphorylation. (B) The provirus load increases with disease progression.

FIGURE 3

Schematic representations of BLV Tax protein mutants and function. (A) Missense mutations between amino acids 240 and 265 containing D247G and S240P influence the transactivation activity of the BLV Tax protein. A putative zinc finger structure (amino acids 30–53) and a leucine-rich activation domain (amino acids 157–197) are also indicated. (B) Multiple functions of the region between amino acids 240 and 265.

FIGURE 4

Proposed mechanism for the regulation of BLV expression and apoptosis induction in TaxD247G-encoded BLV-infected sheep.