Molecular Mechanisms of HTLV-1 Cell-to-Cell Transmission

Abstract

The tumorvirus human T-cell lymphotropic virus type 1 (HTLV-1), a member of the delta-retrovirus family, is transmitted via cell-containing body fluids such as blood products, semen, and breast milk. In vivo, HTLV-1 preferentially infects CD4⁺ T-cells, and to a lesser extent, CD8⁺ T-cells, dendritic cells, and monocytes. Efficient infection of CD4⁺ T-cells requires cell-cell contacts while cell-free virus transmission is inefficient. Two types of cell-cell contacts have been described to be critical for HTLV-1 transmission, tight junctions and cellular conduits. Further, two non-exclusive mechanisms of virus transmission at cell-cell contacts have been proposed: (1) polarized budding of HTLV-1 into synaptic clefts; and (2) cell surface transfer of viral biofilms at virological synapses. In contrast to CD4⁺ T-cells, dendritic cells can be infected cell-free and, to a greater extent, via viral biofilms in vitro. Cell-to-cell transmission of HTLV-1 requires a coordinated action of steps in the virus infectious cycle with events in the cell-cell adhesion process; therefore, virus propagation from cell-to-cell depends on specific interactions between cellular and viral proteins. Here, we review the molecular mechanisms of HTLV-1 transmission with a focus on the HTLV-1-encoded proteins Tax and p8, their impact on host cell factors mediating cell-cell contacts, cytoskeletal remodeling, and thus, virus propagation.

Keywords: HTLV-1; Tax; cell-cell contacts; cell-to-cell transmission; cellular conduit; p8; viral biofilm; virological synapse; virus transmission.

Figure 1

The virological synapse (VS). Interactions of intercellular adhesion molecule 1 (ICAM-1; on HTLV-1-infected T-cells) with lymphocyte function-associated antigen (LFA-1; on target cells), and signals induced by the viral Tax protein trigger polarization of the microtubule organizing center (MTOC) towards the cell-cell contact and formation of the VS at the cell-cell contact. Tax is not only located in the nucleus, but also at the MTOC and in the cell-cell contact region. Tax-induced CREB signaling (nuclear activity of Tax), the accumulation of Tax at the MTOC, and ICAM-1-induced Ras/MEK/ERK signaling are important for MTOC polarization. It is assumed that the VS allows for efficient polarized budding and virus transmission via a synaptic cleft, thus, avoiding recognition of HTLV-1 by the host immune system. Figure was realized thanks to Servier Medical Art.

Figure 2

The viral biofilm. HTLV-1 virions are accumulated in a specialized extracellular matrix (ECM), the so-called viral biofilm, on the surface of infected cells. The viral biofilm is composed of carbohydrates, components of the ECM (collagen, agrin), linker proteins (galectin-3, tetherin), and O-glycosylated surface receptors (CD43, CD45). HTLV-1 particles are concentrated into large, highly infectious assemblies that cluster towards the cell-cell contact. HTLV-1 is transferred to target cells and guarded by the biofilm from immune recognition. Figure was realized thanks to Servier Medical Art.

Figure 3

Cellular conduits. The viral accessory protein p12 is proteolytically cleaved into the p8 protein, which increases adhesion of T-cells through lymphocyte function-associated antigen-1 (LFA-1) clustering. Further, p8 induces polysynapse formation and enhances the number and length of cellular conduits between T-cells, thereby, enhancing HTLV-1-transmission. p8 is transferred to target cells through these conduits and it is hypothesized to induce T-cell anergy in the target cell. This might be a strategy for HTLV-1 to evade the host’s immune surveillance during infection. Host cell proteins that interact with p8 to enhance conduit formation, p8 transfer, and HTLV-1 transmission are still unknown. Figure was realized thanks to Servier Medical Art.

Figure 4

Transmission of HTLV-1 via dendritic cells (DC). DC either capture the virus and transmit it to target cells in the absence of infection (trans-infection), or they are productively-infected before viral transmission (cis-infection). Productive cell-free infection of DC is achieved in vitro by highly-concentrated preparations of cell-free HTLV-1 or by viral biofilms. Figure was realized thanks to Servier Medical Art.

Figure 5

Host factors regulating cellular migration, invasion and conjugate formation. (A) Proteins enhancing cellular migration and/or invasion of HTLV-1-infected cells could favor dissemination of HTLV-1 to target cells. Expression of the Tax-induced small GTP-binding protein GEM enhances both migration of HTLV-1-infected cells and viral transmission. Activity of CRMP2, a phosphoprotein involved in cytoskeleton rearrangement, is modulated by Tax and correlates with migration of infected cells. The actin-bundling protein Fascin is induced by Tax and important for invasive migration of HTLV-1-infected cells. A role of CRMP2 and Fascin for viral transmission remains to be determined. Both Rac-1 and Cdc42 are interaction partners of Tax that are crucial for migration and for MTOC polarization. (B) T-cell conjugate formation, a prerequisite for cell-to-cell transmission depends on components of the cytoskeleton like the Tax-inducible GEM protein, and on Rac1 and Cdc42. Additionally, Tax regulates expression of surface receptors (see Table 1), which are important for cell-cell contact formation, and, potentially, for formation of the VS and HTLV-1 transmission. The influence of different host factors on polarized budding and formation of the VS remains to be determined. Figure was realized thanks to Servier Medical Art.