HTLV-1 persistence and leukemogenesis: A game of hide-and-seek with the host immune system

Abstract

Human T-cell leukemia virus type 1 (HTLV-1), a retrovirus which mainly infects CD4⁺ T cells and causes adult T-cell leukemia/lymphoma (ATL), is primarily transmitted via direct cell-to-cell transmission. This feature generates a wide variety of infected clones in hosts, which are maintained via clonal proliferation, resulting in the persistence and survival of the virus. The maintenance of the pool of infected cells is achieved by sculpting the immunophenotype of infected cells and modulating host immune responses to avoid immune surveillance. Here, we review the processes undertaken by HTLV-1 to modulate and subvert host immune responses which contributes to viral persistence and development of ATL.

Keywords: HLA-II; adult T cell leukemia/lymphoma (ATL); cancer immune response; clonal persistence; human T-cell leukemia virus type 1 (HTLV-1); immune escape; viral immune response.

Figure 1

Natural history of HTLV-1 infection. HTLV-1 primarily infects CD4+ T cells and spread mainly by cell-to-cell transmission via viral synapse. The pool of infected cells are maintained by clonal proliferation which is promoted by Tax, HBZ mRNA and other viral accessory proteins while HBZ protein and host CTLs act to suppress them. Most HTLV-1-infected individuals remain life-long asymptomatic carriers. However, in approximately 5% of infected individuals, acquisition and accumulation of certain mutations leads to malignant transformation of infected cells into adult T-cell leukemia (ATL) cells. Additionally, about 4% of infected individuals develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which is caused by infiltration of infected cells and CTLs into the central nervous system.

Figure 2

Expression pattern of several related genes during HTLV-1 persistence and leukemogenesis. After a long latency period, about 5% of HTLV-1-infected individuals develop ATL. Both Tax and HBZ are critical for leukemogenesis with the HBZ gene being constantly expressed while tax is transcribed in rare, short, self-limiting bursts. Infected cells exhibit increased expression of genes related to T-cell activation (CD25) as well as Treg (FOXP3). Subsequent accumulation of certain mutations during the lifetime of infected clone potentiates leukemic transformation which is accompanied by a loss of CD7 expression and an increase in CADM1 expression. Expression of CD25 and FOXP3, as well as HLA-II, is maintained throughout the latency phase as well as in ATL cells after malignant transformation.

Figure 3

Role of HBZ in immune evasion of infected cells. HBZ induces expression of co-inhibitory molecules to suppress immune activation and confers anti-apoptotic properties by altering expression pattern of pro- and anti-apoptotic proteins. HBZ also induces IL-10 expression in infected cells and antigen presenting cells through TIGIT. IL-10 acts to suppress host immune response as well as enhancing cellular proliferation of infected cells through modulation of STAT signaling by HBZ (not shown).

Figure 4

Hypothetical model on how HTLV-1 hijacks the CIITA-HLA-II axis for immune evasion. (1) Upon induction of Tax either during initial infection or a Tax burst, it promotes CIITA expression as well as further supporting HTLV-1 provirus expression in a positive feedback loop. As the level of Tax increases, so does the levels of CIITA. (2) CIITA induces expression of HLA-II-related genes, leading to upregulation of HLA-II molecules on the cell surface of HTLV-1-infected and ATL cells. This confers an immunosuppressive phenotype to these cells. Additionally, CIITA also binds and sequesters Tax. (3) Working in a negative feedback loop, binding of CIITA and Tax reduces the amount of Tax available for the assembly of promoter complex on the LTR, leading to a reduction in Tax-mediated expression of the HTLV-1 provirus, thus halting Tax expression or burst. Additionally, this also reduces the amount of Tax available for antigen presentation to Tax-specific CTLs, thus reducing CTL activity against HTLV-1. The red question marks in (1) and (2) indicates the points in which the regulation of CIITA in HTLV-1 infection is still unclear; namely (1) how Tax interacts with the promoter of CIITA, and (2) how CIITA and HLA-II expression is maintained throughout the latent period.