Current State of Therapeutics for HTLV-1

Abstract

Human T cell leukaemia virus type-1 (HTLV-1) is an oncogenic retrovirus that causes lifelong infection in ~5-10 million individuals globally. It is endemic to certain First Nations populations of Northern and Central Australia, Japan, South and Central America, Africa, and the Caribbean region. HTLV-1 preferentially infects CD4⁺ T cells and remains in a state of reduced transcription, often being asymptomatic in the beginning of infection, with symptoms developing later in life. HTLV-1 infection is implicated in the development of adult T cell leukaemia/lymphoma (ATL) and HTLV-1-associated myelopathies (HAM), amongst other immune-related disorders. With no preventive or curative interventions, infected individuals have limited treatment options, most of which manage symptoms. The clinical burden and lack of treatment options directs the need for alternative treatment strategies for HTLV-1 infection. Recent advances have been made in the development of RNA-based antiviral therapeutics for Human Immunodeficiency Virus Type-1 (HIV-1), an analogous retrovirus that shares modes of transmission with HTLV-1. This review highlights past and ongoing efforts in the development of HTLV-1 therapeutics and vaccines, with a focus on the potential for gene therapy as a new treatment modality in light of its successes in HIV-1, as well as animal models that may help the advancement of novel antiviral and anticancer interventions.

Keywords: ATL; HAM; HTLV-1; antiviral therapeutics; retrovirus.

Figure 1

Worldwide distribution of HTLV-1 infection. The map specifies the prevalence by region. Created with mapchart.net (2022).

Figure 2

The genomic structure of HTLV-1. The 3′ region is described as the pX region. Tax, rex, and hbz are spliced. Created in BioRender.

Figure 3

The HTLV-1 life cycle in a cell. The virus fuses into the host cell, CD4⁺/CD8⁺ T cells, through interaction with cell surface receptors. The viral core is transported into the cytoplasm where it is reverse transcribed into a double-stranded DNA. This is then transported into the nucleus and integrated into the host genome. The viral proteins are transcribed and translated by the host cell machinery and become infectious after undergoing viral budding. Created in BioRender.

Figure 4

Disease progression of HTLV-1 and the rates of infection. HTLV-1 mostly presents in infected patients as a lifelong subtle immune dysfunction without a defined associated disease, with a broadly estimated 10–30% of populations developing symptomatic HTLV-1-associated disease. There is, however, a broad spectrum of diseases that are reported with infection other than HAM and ATL. Understanding the determinants of if, when, and what disease afflicts infected individuals needs to be further addressed. Created in BioRender.

Figure 5

Mechanisms of siRNA-induced gene silencing. Both RNAi pathways can exert genetic repression by viral and non-viral mechanisms of delivery. PTGS mostly occurs in the cytoplasm as the RISC machinery initiates specific mRNA cleavage. TGS is localised to the nucleus and is mediated by the RITS complex, acting through repressive epigenetic modifications. Ago1, Argonaute 1; Ago2, Argonaute 2; shRNA, short hairpin RNA; RISC, RNA-induced silencing complex; RITS, RNA-induced transcriptional silencing complex; TRBP, transactivating response (TAR) RNA-binding protein; TNRC6, trinucleotide repeat containing 6 protein faily. Created in BioRender.

Figure 6

Routes of administration for nanoparticle delivery of RNAi therapeutics. (A) Chemical modifications, siRNA conjugations, and nanoparticle formulations can be used to improve the outcomes of delivery. Nanoparticle formulation helps to facilitate cell entry and endosomal escape to yield enhanced epigenetic silencing. (B) The different routes of administration for nanoparticle formulation. Created in BioRender.