Latency Reversing Agents: Kick and Kill of HTLV-1?

Abstract

Human T-cell leukemia virus type 1 (HTLV-1), the cause of adult T-cell leukemia/lymphoma (ATLL), is a retrovirus, which integrates into the host genome and persistently infects CD4⁺ T-cells. Virus propagation is stimulated by (1) clonal expansion of infected cells and (2) de novo infection. Viral gene expression is induced by the transactivator protein Tax, which recruits host factors like positive transcription elongation factor b (P-TEFb) to the viral promoter. Since HTLV-1 gene expression is repressed in vivo by viral, cellular, and epigenetic mechanisms in late phases of infection, HTLV-1 avoids an efficient CD8⁺ cytotoxic T-cell (CTL) response directed against the immunodominant viral Tax antigen. Hence, therapeutic strategies using latency reversing agents (LRAs) sought to transiently activate viral gene expression and antigen presentation of Tax to enhance CTL responses towards HTLV-1, and thus, to expose the latent HTLV-1 reservoir to immune destruction. Here, we review strategies that aimed at enhancing Tax expression and Tax-specific CTL responses to interfere with HTLV-1 latency. Further, we provide an overview of LRAs including (1) histone deacetylase inhibitors (HDACi) and (2) activators of P-TEFb, that have mainly been studied in context of human immunodeficiency virus (HIV), but which may also be powerful in the context of HTLV-1.

Keywords: ATLL; HDAC-inhibitor (HDACi); HIV; HTLV-1; P-TEFb; Tax; kick and kill; latency; latency reversing agents (LRA); shock and kill.

Figure 1

The Kick and Kill approach. The Kick and Kill approach presents a treatment option for HTLV-1 infection with the objective to eliminate the CD4⁺ T-cells latently infected with HTLV-1. The “KICK” aims to reactivate viral transcription. Consequently, the immunodominant protein Tax will be presented via MHCI on latently infected cells. CD8⁺ T-cells will mediate the “KILL” of this latent viral reservoir. Abbreviations: CD, cluster of differentiation; HTLV-1, human T-cell leukemia virus type 1; MHC I, major histocompatibility complex class I.

Figure 2

Mode of action of histone deacetylase inhibitors (HDACi) as latency reversing agents for HTLV-1. Epigenetic modifications govern transcription of the integrated HTLV-1 genome. Inhibition of histone deacetylases (HDACs) by histone deacetylase inhibitors (HDACi) raises acetylation of histone tails, thereby decreasing their affinity to chromatin. This results in a more permissive chromatin state, favoring transcriptional activation. Thus, the latent viral reservoir can be reactivated more easily. Abbreviations: HDAC, histone deacetylase; HDACi, histone deacetylase inhibitor; LTR, long terminal repeat; HTLV-1, Human T-cell leukemia virus type 1; Ac, acetylated lysine residue; ${\mathrm{PO}}_4^{3-}$ phosphate ion.

Figure 3

Activators of pTEFb as latency-reversing agents for HTLV-1. The cellular function of the positive transcription elongation factor b (P-TEFb) is to release the RNA Pol II from promoter proximal pausing by phosphorylating Ser2 in the carboxyterminal domain. The level of activity of P-TEFb is governed by its existence in complexes with different cellular proteins. In the inactive high molecular weight complex (HMW), P-TEFb interacts with HEXIM1 and 7SK snRNP; in the low molecular weight complex (LMW), P-TEFb complexes with BRD4, thus, activating transcription. Targeting these complexes to achieve the release of P-TEFb facilitates the binding of P-TEFb to the viral transactivator Tax. The complex of pTEFb and Tax could activate HTLV-1 transcription most effectively, resulting in enhanced Tax protein expression. Additionally, complexes between the P-TEFb-related transcription elongation factor ELL2 and Tax exist. Abbreviations: P-TEFb, positive transcription elongation factor b; 7SK snRNP, 7SK small nuclear ribonucleoprotein; HEXIM1, hexamethylene bisacetamide inducible protein 1; HMBA, hexamethylene bisacetamide; BRD4, bromodomain-containing protein 4; LTR, long terminal repeat; HTLV-1, human T-cell leukemia virus type 1.