Molecular biology of human T cell leukemia virus

Abstract

Human T cell leukemia virus type 1 (HTLV-1) is a horizontally transmitted virus infection of CD4+ lymphocytes which causes adult T cell leukemia-lymphoma (ATLL) and HTLV-associated myelopathy (HAM). The viral genome encodes two oncoproteins, transactivator protein (Tax) and helix basic zipper protein (HBZ), which are considered tumor initiator and maintenance factors, respectively. Tax is the primary inducer of clonal infected T cell expansion, and genetic instability. The immune response to Tax results in the selection of cells with little or no Tax expression, which have undergone genetic and epigenetic alterations that promote T cell activation, proliferation, and resistance to apoptosis. This selection of malignant cells occurs over several decades in 5% of infected individuals. Novel insights into the molecular details of each of these events has led to targeted therapies for ATLL.

Fig 1.

HTLV-1 Genome. The integrated provirus utilizes the promoter in the 5’LTR to drive transcription. This results in an unspliced full length mRNA that serves as genomic DNA to be packaged into virions. It is also used as a template for translation of Gag, Gag-Pr (1 ribosomal frameshift), and Gag-Pr-Pol (2 ribosomal frameshifts) polyproteins. The single spliced mRNA encodes Env that is cleaved into SU and TM envelope proteins. Completely spliced mRNAs encode Tax and Rex. Four accessory protein, p27I, p12I, p13II, and p30II are produced by alternative splicing of ORFs I and II. The p8I protein is a proteolytic cleavage product from p12I. The HBZ proteins are produced from unspliced and spliced mRNAs encoded by minus strand transcripts. Reprinted with permission from Viral Zone

Fig 2.

TCR Activation Pathway in ATLL. The figure depicts percentage of cases in which eachin the pathways is mutated in ATLL. SNVs are depicted in black font, CNVs in white font. Reprinted with permission from reference. This research was originally published in Journal of Biological Chemistry. (c) the American Society for Biochemistry and Molecular Biology.

Fig 3.

Multiple Events of HTLV-1 Infection and Transformation. The schematic hypothesizes that the initia HTLV-1 infected cell is a dendritic cell which presents infectious virus to a T cell. Subsequent expression of Tax, HBZ, and plus strand virus genes result in infection and clonal expansion of other T cells, resulting in genetic heterogeneity, as indicated by different colored cells. Immune responses, as well as viral gene restrictions, result in little or no Tax and plus strand gene product expression from the majority of infected T cells, but a minor population of T cells with transient bursts of Tax expression. Several decades of infection result in selection of cells with specific combinations of genetic and epigenetic alterations that result in adult T-cell leukemia lymphoma.