Molecular Studies of HTLV-1 Replication: An Update

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus discovered. Studies on HTLV-1 have been instrumental for our understanding of the molecular pathology of virus-induced cancers. HTLV-1 is the etiological agent of an adult T-cell leukemia (ATL) and can lead to a variety of neurological pathologies, including HTLV-1-associated-myelopathy/tropical spastic paraparesis (HAM/TSP). The ability to treat the aggressive ATL subtypes remains inadequate. HTLV-1 replicates by (1) an infectious cycle involving virus budding and infection of new permissive target cells and (2) mitotic division of cells harboring an integrated provirus. Virus replication initiates host antiviral immunity and the checkpoint control of cell proliferation, but HTLV-1 has evolved elegant strategies to counteract these host defense mechanisms to allow for virus persistence. The study of the molecular biology of HTLV-1 replication has provided crucial information for understanding HTLV-1 replication as well as aspects of viral replication that are shared between HTLV-1 and human immunodeficiency virus type 1 (HIV-1). Here in this review, we discuss the various stages of the virus replication cycle-both foundational knowledge as well as current updates of ongoing research that is important for understanding HTLV-1 molecular pathogenesis as well as in developing novel therapeutic strategies.

Keywords: antiretroviral; deltaretrovirus; lentivirus.

Figure 1

HTLV-1 life cycle. The major steps in the life cycle of HTLV-1 are shown. A mature, infectious HTLV-1 virion attaches and fuses to the target cell membrane through interaction with the target cell surface receptors GLUT1/HSPG/NRP-1 via the HTLV-1 envelope surface and transmembrane domains of the envelope (Env) protein (A). Following fusion, the viral core containing the viral genomic RNA (gRNA) is delivered into the cytoplasm (B), and during and/or following entry the gRNA genome undergoes reverse transcription to convert the gRNA into double stranded DNA (dsDNA) (C). The dsDNA is then transported into the nucleus (D), and it is integrated into the host genome; (E,F). The provirus is then transcribed by cellular RNA polymerase II (G), as well as post-transcriptionally modified (H). Both full-length and spliced viral mRNAs are exported from the nucleus to the cytoplasm (I). The viral proteins are then translated by the host cell translation machinery (J), and the Gag, Gag-Pol and Env proteins transported to the plasma membrane (PM) along with two copies of the gRNA genome (K). These viral proteins and gRNA assemble at a virus budding site along the PM to form an immature virus particle (L). The budding particle releases from the cell surface (M), and undergoes a maturation process through the action of the viral protease, which cleaves the viral polyproteins to form an infectious, mature virus particle (N).

Figure 2

HTLV-1 Cell-to-Cell Transmission. Shown in the diagram is a host cell (bottom) that has anchored itself to a permissive target cell (top) using ICAM-1 and LFA1. The HTLV-1 accessory protein p8 has been shown to increase the expression of the LFA1 receptors as well as increase the number of cell-cell synapses, which p8 then traffics through to increase LFA1 in the target cell. Once ICAM-1 is bound, it triggers a signaling cascade that leads to the relocation of the MTOC. Additionally, HTLV-1 Tax is found bound to Golgi bodies that are attached to the MTOC. This initiates a variety of cell signaling cascades. For example, one established pathway increases expression of Gem, a protein that increases cell motility and possibly MTOC relocation. As HTLV-1 Gag is produced, it is found concentrated at the MTOC. Subsequently, HTLV-1 Gag is found at the sites of cell-cell contacts where the virus particles bud into the viral synapse formed by the cellular adhesion points. Virus particles produced can bind receptors for entry into the permissive target cell. The question marks along the lines with arrows indicate mechanisms of transport or activation that are not well understood.