The HTLV-1 Virological Synapse

Abstract

Human T-lymphotropic virus-1 (HTLV-1) spreads efficiently between T-cells via a tight and highly organized cell-cell contact known as the virological synapse. It is now thought that many retroviruses and other viruses spread via a virological synapse, which may be defined as a virus-induced, specialized area of cell-to-cell contact that promotes the directed transmission of the virus between cells. We summarize here the mechanisms leading to the formation of the HTLV-1 virological synapse and the role played by HTLV-1 Tax protein. We propose a model of HTLV-1 transmission between T-cells based on the three-dimensional ultrastructure of the virological synapse. Finally, in the light of recent advances, we discuss the possible routes of HTLV-1 spread across the virological synapse.

Keywords: HTLV-1 virological synapse; cytoskeleton; polarization; viral proteins.

Figure 1

Polarization of HTLV-1 proteins and the microtubules network toward the VS formed between autologous CD4+ cells naturally infected with HTLV-1. (A–C) HTLV-1 Gag protein. (D) HTLV-1 Tax protein. (A) Isolated cell. (C–D) autologous CD4+ conjugates. Scale bars = 10μm. Originally published in Journal of Biological Chemistry [35].

Figure 2

Three-dimensional ultrastructure of the VS. Enveloped HTLV-1 virions are trapped in multiple isolated synaptic clefts. Cell-to-cell transmission of HTLV-1 as observed in tomograms of the VS formed between HTLV-1 infected CD4+ T-cell (PBMC) and an autologous uninfected CD4+ T-cell as a target cell. These cells were stained against HTLV-1 Gag p19 matrix protein with a specific monoclonal antibody. (A, B) Projections along the z-axis of two subvolumes of the same tomogram showing viral transmission at two different locations. (C) Surface representation of the VS shown in (A, B): Several virions (blue) are trapped between the closely apposed plasma membranes (yellow). (D) Tomogram slice showing an HTLV-1 particle held between the cell membranes. (E) Surface representation of the virus transmission shown in D (cell membranes: yellow and orange, virus envelope: blue, virus core: magenta). (F, G) Tomogram slices through the two areas of virus transmission shown in (A) and (B), respectively, with a spacing of about 17 nm (F) and 25 nm (G) between subsequent slices. Black arrows indicate a protrusion linking the virus with the cell membrane. (H) Subsequent slices through the area of virus transmission shown in (D) with a spacing of about 17 nm. Black arrows indicate a protrusion linking the virus with the cell membrane. Scale bars: A, B 300 nm, D 500 nm, F, G 100 nm, H 200 nm. This figure was originally published in PLoS One [41].

Figure 3

Illustration of possible routes of HTLV-1 spread between cells in vivo. (A) cell-to-cell transmission via intercellular synaptic cleft surrounded by a tight cell-cell contact between the donor and recipient cell, 1. Cell-free particles can be internalized by dendritic cells and are then transferred to lymphocyte only by cell-to-cell contact, 2. Virus particles can be retained on the cell surface in a biofilm-like-structure before lateral transfer to the recipient outside the cell-cell contact region, 3. (B) In an isolated HTLV-1-infected lymphocyte, the viral proteins are not polarized.