Human T-cell leukaemia virus type 1: parasitism and pathogenesis

Abstract

Human T-cell leukaemia virus type 1 (HTLV-1) causes not only adult T-cell leukaemia-lymphoma (ATL), but also inflammatory diseases including HTLV-1-associated myelopathy/tropical spastic paraparesis. HTLV-1 transmits primarily through cell-to-cell contact, and generates abundant infected cells in the host in order to survive and transmit to a new host. The resulting high proviral load is closely associated with the development of ATL and inflammatory diseases. To increase the number of infected cells, HTLV-1 changes the immunophenotype of infected cells, induces proliferation and inhibits apoptosis through the cooperative actions of two viral genes, tax and HTLV-1 bZIP factor (HBZ). As a result, infected cells survive, proliferate and infiltrate into the tissues, which is critical for transmission of the virus. Thus, the strategy of this virus is indivisibly linked with its pathogenesis, providing a clue for prevention and treatment of HTLV-1-induced diseases.This article is part of the themed issue 'Human oncogenic viruses'.

Keywords: HBZ; HTLV-1; Tax.

Figure 1.

Structure of HTLV-1 provirus and its encoded genes. HTLV-1 provirus contains gag, pol, and env genes that encode structural proteins. In addition, tax, rex, p12, p13 and p30 are transcribed from the plus strand of the provirus. HTLV-1 bZIP factor (HBZ) is transcribed as antisense transcripts. The blue bar in the HBZ coding region shows the CTCF binding site.

Figure 2.

Natural history of HTLV-1 infection. HTLV-1 transmits via three different routes: (i) breast-feeding, (ii) sexual intercourse, and (iii) the parenteral route. After infection, the virus increases the number of infected cells in vivo through the actions of Tax and HBZ. The host immune response suppresses HTLV-1-infected cells, mainly through lysis by virus-specific cytotoxic T lymphocytes (CTLs). HTLV-1-infected cells possess the immunophenotype of effector/memory T cells, which migrate into breast milk and semen; these infected cells can transfer infection to the new host. Between 5% and 10% of HTLV-1-infected individuals develop ATL or inflammatory diseases. STD, sexually transmitted disease.

Figure 3.

Schematic depiction of HTLV-1 clonality over the course of infection. Each line on the figure represents the growth of one HTLV-1⁺ T-cell clone; the grey shaded area represents a large number of lower-abundance clones. The red dashed line shows the growth trajectory of a clone that undergoes malignant transformation after 50 years; the red asterisks denote the acquisition of tumour driver mutations; in ATL these are frequent in certain signalling pathways: T-cell receptor; NFκB; CCR4; p53; and Notch-1 [–87]. The pre-malignant clone is shown to originate in early infection; this is likely [31,88], but not necessary. During the first few weeks of infection, before the emergence of an effective cytotoxic T-lymphocyte response, the virus spreads rapidly by cell-to-cell contact through the virological synapse; the number of clones of infected T lymphocytes typically rises to 10⁴ to 10⁵ when the proviral load set-point is reached, after approximately one to two months [23,89]. In the chronic phase of infection, CTLs restrict this infectious mode of spread [44], and the proviral load is maintained by continued proliferation of existing clones. In this phase, there is a quasi-equilibrium between viral propagation and the host immune response; while the proviral load remains approximately constant, the abundant clones grow in abundance and the low-abundance clones shrink, leading to a progressive rise in the oligoclonality index [37]. The abundant clones appear to last for the lifetime of the host [37]. During chronic infection the abundant, persistently activated anti-Tax CTL response demonstrates that Tax expression is frequent in vivo [45]. Since Tax expression is normally undetectable in fresh PBMCs, we infer that Tax expression is intermittent in vivo. Virus-specific CTLs may persist during active ATL; it remains to be tested whether boosting the CTL response can be used as an adjunct to therapy. Constant cell division leads to the accumulation of replicative mutations, which increase the probability of malignant transformation [90]. ATL usually arises after 4–6 decades of infection, and so is more frequent in individuals infected during childhood. The risk of ATL may also be correlated with the proviral load, which in turn is correlated with the number of HTLV-1-infected T-cell clones, not with the degree of oligoclonality [37].

Figure 4.

Leukaemogenesis by viral genes, genetic and epigenetic alterations. About 5% of HTLV-1-infected individuals develop ATL after a long latent period. (a) Tax and HBZ play critical roles in leukaemogenesis by HTLV-1. HBZ is constantly expressed while the tax gene is sporadically transcribed. Tax and HBZ modulate the immunophenotype of ATL cells, inhibit apoptosis and promote proliferation. HBZ is expressed in all ATL cases while tax is not expressed in approximately half of ATL cases. (b) Subsequent genetic and epigenetic alterations that accumulate during the long lifetime of the infected clone fix or potentiate these phenotypic and functional changes. (c) For example, HBZ induces CCR4 expression, which leads to increased migration and proliferation of infected cells. Gain-of-function mutations of CCR4 were found in approximately 20% of ATL cases. Similarly, Tax strongly activates NFκB. Increased miR31 expression leads to NFκB activation in the absence of Tax.