How does HTLV-1 cause adult T-cell leukaemia/lymphoma (ATL)?

Abstract

A typical person infected with the retrovirus human T-lymphotropic virus type 1 (HTLV-1) carries tens of thousands of clones of HTLV-1-infected T lymphocytes, each clone distinguished by a unique integration site of the provirus in the host genome. However, only 5% of infected people develop the malignant disease adult T cell leukaemia/lymphoma, usually more than 50 years after becoming infected. We review the host and viral factors that cause this aggressive disease.

Figure 1

Genome structure of the HTLV-1 provirus. The gag, pr, pol, and env genes are shown flanked by long terminal repeat (LTR) sequences. The pX regions includes regulatory genes encoding Tax, Rex, p21, p12, p13, and p30, as well as the antisense gene encoding HBZ. Modified from [1].

Figure 2

Frequency distribution of HTLV-1-infected T-cell clones in different manifestations of HTLV-1 infection. Each pie-chart shows the clones identified in 10 μg of genomic DNA from the peripheral blood mononuclear cells of a single representative host. The size of each sector represents the relative abundance of that clone in the individual's proviral load. The oligoclonality index (OCI) (also known as the Gini index) is a measure of the non-uniformity of the frequency distribution (71). OCI = 0 implies that all clones have the same frequency; OCI = 1 implies that only a single clone is present. These data were reported in Figure 2A of Gillet et al. [71].

Figure 3

Factors that determine the risk of ATL. These factors may be divided into three categories: host-specific factors, clone-specific, and stochastic factors. The host-specific factors — host genotype, age at infection, and certain co-infections [84], especially Strongyloides stercoralis — are independent of the proviral integration site. Persistent replication of long-lived infected clones, driven by Tax and HBZ, may lead to the accumulation of replicative mutations [75], whose frequency is strongly correlated with the risk of malignant transformation. This may explain the observed association between ATL and infection with HTLV-1 in early childhood. The clone-specific oncogenic factors depend on the proviral integration site: spontaneous proviral expression is influenced by the flanking host genome [72]; and the HTLV-1 gene products, especially Tax and HBZ, promote the proliferation and longevity of existing clones and genetic instability. It is possible that insertional mutagenesis contributes to oncogenesis, by activation or disruption of host genes flanking the provirus or via long-range chromatin interactions. Finally, infected T cell clones that are specific to persistent and abundant antigens, such as CMV or Strongyloides antigens, may enjoy an additional proliferative advantage. It is widely assumed [85] that secondary mutations — the stochastic factors — increase the proliferative or survival advantage of an HTLV-1⁺ clone, and contribute to malignant transformation. Direct evidence to substantiate this assumption is needed from whole-genome sequencing of ATL clones. Preliminary work along this line has already begun, with evidence that mutations in three signalling pathways — NF-κB, T-cell receptor and CCR4 — are associated with ATL [86^••]. * Tax expression is lost in the malignant clone in ~50% of cases of ATL.