Human T-cell leukemia virus type 1 (HTLV-1) and leukemic transformation: viral infectivity, Tax, HBZ and therapy

Abstract

The human T-cell leukemia virus type 1 (HTLV-1) was the first retrovirus discovered to be causative of a human cancer, adult T-cell leukemia. The transforming entity of HTLV-1 has been attributed to the virally-encoded oncoprotein, Tax. Unlike the v-onc proteins encoded by other oncogenic animal retroviruses that transform cells, Tax does not originate from a c-onc counterpart. In this article, we review progress in our understanding of HTLV-1 infectivity, cellular transformation, anti-sense transcription and therapy, 30 years after the original discovery of this virus.

Figure 1. Genome structure of the HTLV-1 provirus

The gag, pol, and env structural genes are flanked by 5′ and 3′ long terminal repeats (LTRs). The pX region, Tax, Rex, and the antisense HTLV-1 basic leucine zipper factor (HBZ) open reading frame are shown. Drawing is intended to be illustrative and not to exact scale. This drawing is modified after (Matsuoka and Jeang 2007).

Figure 2. Cell surface proteins that participate in HTLV-1 virion infection

Interaction of HTLV-1 particles with HSPG, NRP-1 and Glut-1 proteins is schematized. Please see text for more detail.

Figure 3. Putative cellular events that are important for ATL development

HTLV-1 infects either CD4+ cells or a hematopoietic progenitor cell. Infected cells activate survival pathways NF-κB and Akt to evade apoptosis and senescence. Inactivation of p53 and activation of CDKs accelerate cellular proliferation. Tax attenuation of the spindle assembly checkpoint protein, Mad1, Tax reduction of DNA-damage repair, and Tax activation of reactive oxygen species (ROS) lead to aneuploidy and clastogenic damage. Late in ATL development when Tax expression is extinguished HBZ, microRNA changes, and TP53INP1 inactivation may be important to achieve a fully transformed phenotype.

Figure 4. Therapeutic approaches for ATL

Current therapeutic strategies for Acute or Lymphoma-type ATL and Chronic or Smoldering ATL are listed.