Distinct functions of HTLV-1 Tax1 from HTLV-2 Tax2 contribute key roles to viral pathogenesis

Abstract

While the human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATL), to date, its close relative HTLV-2 is not associated with ATL or other types of malignancies. Accumulating evidence shows that HTLV-1 Tax1 and HTLV-2 Tax2 have many shared activities, but the two proteins have a limited number of significantly distinct activities, and these distinctions appear to play key roles in HTLV-1 specific pathogenesis. In this review, we summarize the functions of Tax1 associated with cell survival, cell proliferation, persistent infection as well as pathogenesis. We emphasize special attention to distinctions between Tax1 and Tax2.

Figure 1

Structures of HTLV-1 and HTLV-2. A comparison of HTLV-1 genes with those of HTLV-2. Some HTLV-2 non-structural genes such as APH-2, the equivalent protein to HTLV-1 HBZ, are indicated as HBZ and are named using HTLV-1 nomenclature in this figure.

Figure 2

Two regions of Tax1 are responsible for increased transforming activity relative to Tax2 in CTLL-2 cells. (A) The amino acid sequences of the Tax LZR of HTLVs and STLVs. A bar indicates the identical amino acids of Tax from the other six viruses to that of Tax1. The leucine residues constituting a putative LZ structure are marked by circle. (B) The amino acid sequences in the C-terminal ends of the respective Tax proteins. The PBMs are surrounded by squares.

Figure 3

A model for HTLV-1-specific pathogenesis. The amounts of IL-2 or similar T-cell growth-promoting cytokines are low in vivo. In such environment, HTLV-1 infected cells proliferate more efficiently than HTLV-2 infected cells, and have greater probability to acquire genetic and/or epigenetic mutations. In addition, increased proliferation of HTLV-1 infected T-cells would effectively deteriorate the host immune system. Once such mutated cells accumulate with a reduced host immune activity, HTLV-1-infected T-cells can grow monoclonally, resulting in ATL development. For HAM/TSP, an increase in HTLV-1-infected cells in vivo induces more immune response to HTLV-1, especially to Tax1, resulting in HAM/TSP development through an autoimmune mechanism.