HTLV-1 clonality in adult T-cell leukaemia and non-malignant HTLV-1 infection

Abstract

Human T lymphotropic virus type 1 (HTLV-1) causes a range of chronic inflammatory diseases and an aggressive malignancy of T lymphocytes known as adult T-cell leukaemia/lymphoma (ATLL). A cardinal feature of HTLV-1 infection is the presence of expanded clones of HTLV-1-infected T cells, which may persist for decades. A high viral burden (proviral load) is associated with both the inflammatory and malignant diseases caused by HTLV-1, and it has been believed that the oligoclonal expansion of infected cells predisposes to these diseases. However, it is not understood what regulates the clonality of HTLV-1 in vivo, that is, the number and abundance of HTLV-1-infected T cell clones. We review recent advances in the understanding of HTLV-1 infection and disease that have come from high-throughput quantification and analysis of HTLV-1 clonality in natural infection.

Keywords: Clonality; HTLV-1; High-throughput sequencing; Integration; Leukaemia; Lymphoma; Persistent infection; Retrovirus.

Fig. 1

Structure and coding potential of plus- and minus-strand HTLV-1 mRNAs. ^©The American Society of Hematology.

Fig. 2

The fraction of cells in each HTLV-1-infected T-cell clone that spontaneously expresses the Tax protein is negatively correlated with the abundance of the clone in vivo (P < 10⁻¹⁶, chi-squared test for trend).

Fig. 3

Clone frequency distribution of HTLV-1-infected T cells in a representative subject (Patient 1) with non-malignant HTLV-1 infection and a representative case (Patient 2) of ATLL. Upper panels depict the number of cells detected in each clone in a sample of genomic DNA from peripheral blood mononuclear cells, in descending order of clone abundance. In the inset pie charts, the size of each sector depicts the relative abundance of the respective clone; the solid black sector denotes a large number of low-abundance clones. Lower panels show the cumulative fraction of the proviral load constituted by the infected T-cell clones. The oligoclonality index, OCI, is defined as OCI = A/(A + B).

Fig. 4

Rapid emergence of ATLL. In February 2009, one clone (shaded blue) dominated the infected cell population present in the peripheral blood of an infected person. However, the clone that underwent malignant transformation to cause ATLL 18 months later was a minor clone, occupying only 0.04% of the proviral load at this date. Such cases suggest that clonal expansion per se of HTLV-1⁺ cells does not predispose to malignant transformation.

Fig. 5

Model of the development of ATLL. HTLV-1 infection constitutes the first hit that predisposes each infected T-cell to malignant transformation. The probability that a given clone undergoes transformation depends principally on the balance of two opposing forces: negative selection by the host CTL response to HTLV-1 antigens, and persistent or repeated expression of two regulatory genes of HTLV-1, tax and HBZ, whose products prolong the lifespan of the T-cell clone and so increase the chance of accumulation of further genetic or epigenetic hits. These further hits may cause constitutive activation of the pathways initially activated by Tax, after which loss of Tax expression confers a survival advantage on the clone by escape from the strong anti-Tax CTL response. In contrast to the frequent silencing of Tax expression, HBZ expression appears to persist ; an effective CTL response to HBZ reduces the proviral load and the risk of HAM/TSP, and may reduce the risk of ATLL.