key: cord-0035646-2zms2oyx authors: Garcia, Eduardo; Piguet, Vincent title: Virological Synapse for Cell-Cell Spread of Viruses date: 2006 journal: Cell-Cell Channels DOI: 10.1007/978-0-387-46957-7_22 sha: 43e53f6063f0ae3d22c08fd9c473446a2384b36a doc_id: 35646 cord_uid: 2zms2oyx Cell-to-cell spread of retroviruses via virological synapse (VS) contributes to overall progression of disease. VS are specialized pathogen-induced cellular structures that facilitate cell-to-cell transfer of HIV-1 and HTLV-1. VS provide a mechanistic explanation for cell-associated retroviral replication. While VS share some common features with neurological or immunological synapses, they also exhibit important differences. The role of VS might not be limited to human retroviruses and the emerging role of a plant synapse suggests that VS might well be conserved structures for cell-cell spreading of both animal and plant viruses. Dissection of the VS is just at its beginning, but already offers ample information and fascinating insights into mechanisms of viral replication and cell-to-cell communication. order to permit immune responses to take place, ISs need to be assembled and disassembled quickly. An example is CTL-mediated killing, where a single effector cell has been shown to contact sequentially target cells through several stable IS (for reviews see in refs. 1, [5] [6] [7] . In recent years, the concept of the synapse has been further extended to cell-cell contacts during viral replication. To initiate an infection, viruses need to gain access to the replicative machinery of the host cell. In the cell-free virus model, viruses do so by crossing the plasma membrane of the target cell after binding to surface receptors. Nevertheless, some viruses use direct passage from cell-to-cell to spread within their host achieving, in the process, protection from neutralizing anti-bodies^ and complement as well as higher kinetics of replication (reviewed in ref 9 ). Recent articles have described virological synapses (VS) for two retroviruses, human T cell leukemia virus type 1 (HTLV-1) and human immunodeficiency virus type 1 (HIV-l)^°-^5 (reviewed in ref 16) . VS, like their neural and immunological counterparts, suit the minimal criteria that define a synapse: both pre and post-synaptic cells implied in cell-cell contact remain discrete cells (no plasma membrane fusion), a stable adhesive connection is established between the two cells and directed transmission of information (viral genome) occurs from the infected cell (presynaptic cell) to the uninfected cell (post-synaptic). Although viral cell-to-cell transfer has been identified many years ago,^'^^'"^® we gained only recently some insight into the mechanisms of this mode of viral transmission. Cell-free HTLV-1 ineffectively infects T lymphocytes and spreads within and between individuals via cell-to-cell transfer. With the partial unraveling of the mechanisms involved in HTLV-1 dissemination from lymphocyte to lymphocyte via VS,^®'^^'^^ puzzling questions, such as HTLV-1 cell tropism, regardless of the ubiquitous expression of its surface receptor, have found satisfying explanations. Other retroviruses, such as HFV-l and SIV, also use VS to propagate within their respective hosts. Efficient HFV-l infection requires permissive target cells to be located in close vicinity in order to initiate infection and subsequent spreading throughout different tissues. At least three modes of propagation have been described for HIV-1. Firstly, cell-free transmission of HIV-1 is well characterized. Cell-free HIV-1 binds surface receptors/coreceptors (CD4/CCR5 and CXCR4) of permissive cells before fusing with the plasma membrane of the target cell and following the subsequent steps of the viral replication cycle. Secondly, HIV is able to propagate through infection in trans. Cells such as dendritic cells (DC) capture virions through viral binding to cell-surface receptors such as C-type lectins. HIV-l^ DCs, not necessarily infected themselves, then present the virus to target cells in trans via a VS or an Infectious Synapse. Thirdly, HFV-l -infected cells (also termed effector cells) are able to transmit the virus to uninfected target cells, without the previous requirement of virus budding in the extracellular milieu, illustrating direct cell-to-cell viral transmission through a VS. ^"^ Until now, three types of VS have been described for HFV-l: the DC-T cell VS, also referred to as "Infectious Synapse", ' the T cell-T cell VS and the mononuclear cell-mucosal epithelial VS, impUcated in HFV transcytosis through mucosal epithelia.^^'^^ The use of VS for viral transmission is probably not limited to retroviruses and is exploited by other intracellular pathogens in order to disseminate through their host. Early in vitro experiments show a VS-like structure possibly contributing to SARS-coronavirus (SARS-CoV) dissemination from DCs to target cells.^ As the concept of infectious or virological synapse is further applied to other organisms, such as plants,^^ VS emerges as a general mechanism of cell-to-cell transmission for many pathogens and parasites. In model systems of sexual transmission, myeloid dermal DCs and Langerhans cells (LC) play a central role in the early steps of HFV-l propagation (reviewed in refs. [36] [37] [38] [39] [40] . DCs locate to the skin and mucosal tissues in an immature state (iDC) until coming across pathogen-derived antigens. DC activation and diflFerentiation into mature APC^^-^^ results from contact with different stimuli such as bacterial products, TNF family ligands, ^' double-stranded ^ and single-stranded RNA. Migration of mature DCs (mDC) from the periphery to secondary lymphoid organs is strongly associated with maturation and allows DCs to encounter antigen-specific T cells in order to initiate adequate immune responses. ^'^^ Although HIV-l infects CD4^T cells more effectively, LC and other DC types support low levels of viral replication, both in vivo and in vitro. ^ '^^ DC are also able to capture HIV-l in an infectious form and transfer such virions to target CD4*T cells without the need of virus replication within the effector cell (here the DC)^^'^^' (reviewed in refs. 37,61). The dissection of the DC-T cell VS is still ongoing and many questions remain to be answered. Is VS formation relevant in the context of sexual transmission of HIV-1? Shown to facilitate nonreplicative HIV-1/SIV transfer in DC-T cell conjugates,^^'^^'^^ DC-T cell VS usage by HIV-1 has to be confirmed with replicative CCR5-using strains. What is the relationship between the DC-T cell immunological synapse and the DC-T cell VS. ** The molecular basis of DC-T cell VS assembly remains poorly understood. Interference studies using receptor-blocking antibodies, inhibitors of cellular processes involved in cytoskeletal rearrangements and signaling, and RNA interference of surface receptor expression are ongoing in order to address this issue. Synapse Upon cell-to-cell contact, HIV-l-infected T cells are able to induce rapid clustering of viral receptors on uninfected T cells.^^'^"^ The molecular interactions behind this process were recently detailed and led to the description of an HIV-l induced VS between T cells. ^"^ Interactions between HIV-l Env protein on the effector cell with CD4 and CXC chemokine receptor 4 (CXCR4) on the naive T cell are essential to induce a fast actin-dependent recruitment of viral receptors and lymphocyte-associated antigen 1 (LFA-1) to the VS.^"^ F-actin disassembly/reassembly is central to the mobilization of all players within the T cell VS, as demonstrated by inhibitors for both processes. ^"^ Indeed, stable antigen-independent clusters between CD4^T cells seldom occur when compared with antigen-dependant DC-T cell clusters. Therefore, stabilization of T cell-T cell contacts must be triggered by a specific signal. In the case of HIV-l VS, Env seems to function as the triggering signal. Blocking antibodies and chemical inhibitors preventing Env binding to CD4 and CXCR4 on the naive T cell reduce T cell VS formation as well as T cell-T cell conjugates. ^"^ Epithelia Mucosal epithelia are the first line of defense of the human body against sexual transmission of HIV-1. The virus needs to circumvent this obstacle in order to gain a foothold within a new individual. In addition to capture by DCs or Dendritic Cells residing in mucosal epithelia, transcytosis of infectious virions across epithelial cells at mucosal sites of exposure may well be a strategy used by HIV-1. Early studies showed convincingly that transcytosis with cell-associated HIV-l was much more efficient than transcytosis of cell-free virions through epithelial cell layers. ^^'^^'^^ Virological synapses, in which HIV-1-infected blood mononuclear cells establish contacts with mucosal epithelial cells, were recently described, providing a likely explanation for this cell-to-cell vial transmission. In this context, HIV-l buds locally from the effector cell, followed by endocytosis and transcytosis without fusion from the apical to the serosal pole of epithelial cells.^^ Infection grants HIV-l-loaded cells the ability to interact with epithelial cells by upregulating the expression of surface adhesion molecules^ and by the presence of the viral envelope proteins gpl20 and gp4l. Epithelial cells also take part in VS formation and stabilization as well as in proper initiation of HIV-l transcytosis. The heparan sulfate proteoglycan (HSPG) agrin, present in the scaffolding complexes of neural and immunological synapses, ' serves as an HIV-1 attachment receptor through gp4l-binding, reinforcing virion interactions with its previously described endocytic receptor galactosyl ceramide (GalCer).^^ Nevertheless, this is not sufficient to initiate HIV-l trancytosis and additional signals supplied by the synaptic scaffold are crucial. Stable interactions between epithelial cells and HIV-1-infected PBMCs result partially from epithelial expression of the RGD-dependant Beta-1 integrin. Contacts between RGD-containing molecules, either at the surface of HIV-l-infected PBMCs or released as soluble factors,^ with Beta-1 integrins potentially initiate the signaling pathways leading to an efficient HIV-l trancytosis and its subsequent spread throughout the host.^ These three examples of HIV-l VS demonstrate that VS play a central role in HIV cell-to-cell transmission. The benefit of VS for HIV spread is observed so far in vitro, but suggests an important function for VS in vivo. HTLV-1 is an oncogenic retrovirus spreading from infected T lymphocytes to uninfected T lymphocytes through VS, with little if any contribution from cell-free virions.^^ Upon cell-to-cell that Tax synergizes with ICAM-1 engagement to cause microtubule reorientation during VS formation.'^^ Finally, the recent identification of HTLV-1 receptor, glucose transport protein 1 (GLUT-1), will certainly lead to further understanding of the mechanisms involved in HTLV-1 T cell VS formation. Passage of intracellular pathogens, such as viruses, bacteria and parasites, between animal cells has been an area of intense scrutiny (reviewed in refs. 9,105,106). Thus it is likely that the concept of virological synapse or rather infectious synapse might be extended beyond animal viruses described above. Recently, the concept of synapse, including the VS has been extended to plants.^^ Plant viruses are known to take advantage of plasmodesmata to gain access to the next cell. Plasmodesmata are cytoplasmic channels formed and maintained between neighboring plant cells^^^'^®^ diat selectively allow passage of macromolecules as well as viral particles. In a physiological context, plant synapses share limited similarities with the mammalian neuronal as well as immunological synapse, allowing plants to deal with pathogen attacks, as well as establishing symbiotic interactions, by polarizing the endocytic and secretory machineries towards the intruding organisms (reviewed in ref 35) . The use of a VS-like structure in plants, impUcating genetic transfer from one discrete cell to another has been recendy demonstrated in the case of Tobacco Mosaic Virus (TMV), supporting the concept ofVS in plants. ^^^ Unlike HIV-1 DC-T cell VS that originates in tetraspanin rich multivesicular endosomes (MVB), TMV replication originates in the endoplasmic reticulum, before cell-to-cell propagation across plasmodesmata.^®^ There are significant differences between the VS of mammalian viruses when compared to VS-like structures in plants. Plasmodesmata are membrane Hnked pores in plant cell walls that provide continuity between adjacent cells, whereas in the immune system contacts between cells are transient and do not necessitate the formation of a pore. Nevertheless, cell-to-cell propagation of TMV through a plant VS-like structure is very reminiscent of the VS of mammalian retroviruses. The identification and characterization of the virological synapse provides a satisfying explanation for cell-cell spread of retroviruses within the immune system. VS contribute to stealthy retroviral replication as these viruses hop from cell-to-cell across VS without possibility of neutralization by the immune system. Plant viruses use a plant VS-like structure, indicating that VS are conserved evolutionary structures facilitating replication of animal as well as plant viruses. For each virus and cellular context VS present themselves differendy. Only in-depth study of VS in its various forms will provide us with a useful knowledge that may potentially allow us to interrupt cell-cell viral spread. Neural and immunological synaptic relations A synaptic basis for T-lymphocyte activation Regulation of B-lymphocyte activation, proliferation, and differentiation The secretory synapse: The secrets of a serial killer What is the importance of the immunological synapse? Control of immune responses by trafficking cell surface proteins, vesicles and lipid rafts to and from the immunological synapse T-cell-antigen recognition and the immunological synapse Infection of specific dendritic cells by CCR5-tropic HIV-1 promotes cell-mediated transmission of virus resistant to broadly neutralizing antibodies Directed egress of animal viruses promotes cell-to-cell spread Spread of HTLV-I between lymphocytes by virus-induced polarization of the cytoskeleton Recruitment of HIV and its receptors to dendritic cell-T cell junctions HIV-1 cell-to-cell transfer across an Env-induced, actin-dependent synapse Immunodeficiency virus uptake, turnover, and 2-phase transfer in human dendritic cells DC-SIGN-mediated infectious synapse formation enhances X4 HIV-1 transmission from dendritic cells to T cells HIV-1 trafficking to the dendritic cell-T-cell infectious synapse uses a pathway of tetraspanin sorting to the immunological synapse Dangerous liaisons at the virological synapse Ceil-to-cell transmission of human immunodeficiency virus type 1 in the presence of azidothymidine and neutralizing antibody Cell-to-cell spread of HIV-1 occurs within minutes and may not involve the participation of virus particles The role of cell-to-cell transmission in HIV infection Rapid and efficient cell-to-cell transmission of human immunodeficiency virus infection from monocyte-derived macrophages to peripheral blood lymphocytes Engagement of specific T-cell surface molecules regulates cytoskeletal polarization in HTLV-1-infected lymphocytes Human T-lymphotropic virus, type-1, tax protein triggers microtubule reorientation in the virological synapse HIV-1 entry and its inhibition Novel therapies based on mechanisms of HIV-1 cell entry Where does HIV live? Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses Syndecan captures, protects, and transmits HIV to T lymphocytes Involvement of macrophage mannose receptor in the binding and transmission of HIV by macrophages Diversity of receptors binding HIV on dendritic cell subsets Blockade of attachment and fusion receptors inhibits HIV-1 infection of human cervical tissue HIV-1-infected blood mononuclear cells form an integrinand agrin-dependent viral synapse to induce efficient HIV-1 transcytosis across epithelial cell monolayer Transcytosis of infectious human immunodeficiency virus across a tight human epithe-Hal cell hne barrier Intracellular neutralization of HIV transcytosis across tight epithelial barriers by anti-HIV envelope protein dIgA or IgM pH-dependent entry of severe acute respiratory syndrome coronavirus is mediated by the spike glycoprotein and enhanced by dendritic cell transfer through DC-SIGN Plant synapses: Actin-based domains for cell-to-cell communication Inhibiting sexual transmission of HIV-1 infection Transmission, acute HIV-1 infection and the quest for strategies to prevent infection The interaction of immunodeficiency viruses with dendritic cells The role of dendritic cell C-type lectin receptors in HIV pathogenesis A novel HIV receptor on DCs that mediates HIV-1 transmission Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane T-cell engagement of dendritic cells rapidly rearranges MHC class II transport Activation of lysosomal function during dendritic cell maturation Coordinated events during bacteria-induced DC maturation GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells Fas engagement induces the maturation of dendritic cells (DCs), the release of interleukin (XL)-1 beta, and the production of interferon gamma in the absence of XL-12 during DC-T cell cognate interaction: A new role for Fas ligand in inflammatory responses Inflammatory stimuli induce accumulation of MHC class XX complexes on dendritic cells Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8 Dendritic cells and the control of immunity Xmmunobiology of dendritic cells Regulation of T cell immunity by dendritic cells Dynamic imaging of T cell-dendritic cell interactions in lymph nodes T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases Epidermal Langerhans cells-a target for HTLV-IXX/IAV infection Cellular localization of simian immunodeficiency virus in lymphoid tissues. X. Xmmunohistochemistry and electron microscopy Rapid infection of oral mucosal-associated lymphoid tissue with simian immunodeficiency virus Simian immunodeficiency virus rapidly penetrates the cervicovaginal mucosa after intravaginal inoculation and infects intraepithelial dendritic cells Differential susceptibihty to human immunodeficiency virus type 1 infection of myeloid and plasmacytoid dendritic cells Productive infection of dendritic cells by XiIV-1 and their ability to capture virus are mediated through separate pathways Myeloid and plasmacytoid dendritic cells transfer HXV-1 preferentially to antigen-specific CD4+ T cells Essential roles for dendritic cells in the pathogenesis and potential treatment of HXV disease Efficient virus transmission from dendritic cells to CD4+ T cells in response to antigen depends on close contact through adhesion molecules Presence of host ICAM-1 in human immunodeficiency virus type 1 virions increases productive infection of CD4+ T lymphocytes by favoring cytosolic delivery of viral material DC-SXGN, a dendritic cell-specific HXV-1-binding protein that enhances trans-infection of T cells Lentivirus-mediated RNA interference of DC-SXGN expression inhibits human immunodeficiency virus transmission from dendritic cells to T cells A dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN)-related protein is highly expressed on human liver sinusoidal endothelial cells and promotes HXV-1 infection DC-SIGN interactions with human immunodeficiency virus: Virus binding and transfer are dissociable functions DC-SXGN (CD209) mediates dengue virus infection of human dendritic cells Human cytomegalovirus binding to DC-SIGN is required for dendritic cell infection and target cell trans-infection C-type lectins DC-SIGN and L-SIGN mediate cellular entry by Ebola virus in cis and in trans Dendritic cells: Specialized and regulated antigen processing machines DC-SIGN-mediated internalization of HIV is required for trans-enhancement of T cell infection DC-SIGN promotes exogenous MHC-I-restricted HIV-1 antigen presentation Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate HIV-1-infected monocyte-derived dendritic cells do not undergo maturation but can elicit IL-10 production and T cell regulation Human immunodeficiency virus type 1 gpl20 induces abnormal maturation and functional alterations of dendritic cells: A novel mechanism for AIDS pathogenesis TsglOl and the vacuolar protein sorting pathway are essential for HIV-1 budding HIV-1 and Ebola virus encode small peptide motifs that recruit TsglOl to sites of particle assembly to facilitate egress AIPl/ALIX is a binding partner for HIV-1 p6 and EIAV p9 functioning in virus budding The protein network of HIV budding Infectious HIV-l assembles in late endosomes in primary macrophages HIV interaction with endosomes in macrophages and dendritic cells Dendritic cells exposed to human immunodeficiency virus type-1 transmit a vigorous cytopathic infection to CD4+ T cells Conjugates of dendritic cells and memory T lymphocytes from skin facilitate productive infection with HIV-1 Functional antigen-independent synapses formed between T cells and dendritic cells Normal development but differentially altered proliferative responses of lymphocytes in mice lacking CD81 Cutting edge: Dynamic redistribution of tetraspanin CD81 at the central zone oi the immune synapse in both T lymphocytes and APC The tetraspanin web modulates immune-signalling complexes Tetraspanin CD81 provides a costimulatory signal resulting in increased human immunodeficiency virus type 1 gene expression in primary CD4+ T lymphocytes through NF-kappaB, NFAT, and AP-1 transduction pathways Mechanism of HIV spread from lymphocytes to epithelia The role of CD4 in HIV binding and entry Unidirectional budding of HIV-1 at the site of cell-to-cell contact is associated with copolarization of intercellular adhesion molecules and HIV-1 viral matrix protein Entry of viruses through the epithelial barrier: Pathogenic trickery Enhanced HIV replication in monocytic cells following engagement of adhesion molecules and contact with stimulated T cells New insights into the roles of agrin HIV-1 Tat protein and endothelium: From protein/cell interaction to AIDS-associated pathologies The immune control and cell-to-cell spread of human T-lymphotropic virus type 1 The immunological synapse of CTL contains a secretory domain and membrane bridges Surface contact requirements for activation of cytotoxic T lymphocytes Cytoskeletal polarization of T cells is regulated by an immunoreceptor tyrosine-based activation motif-dependent mechanism LFA-1, and CD28 play unique and complementary roles in signaling T cell cytoskeletal reorganization The human T-cell leukemia virus type 1 transactivator protein Tax colocalizes in unique nuclear structures with NF-kappaB proteins Localization of human T-cell leukemia virus type 1 tax to subnuclear compartments that overlap with interchromatin speckles The ubiquitous glucose transporter GLUT-1 is a receptor for HTLV Bacterial invasion: The paradigms of enteroinvasive pathogens Intracellular parasite invasion strategies Gatekeepers for cell-to-cell transport of developmental signals in plants Getting the message across: How do plant cells exchange macromolecular complexes? Tobacco mosaic virus infection spreads cell to cell as intact rephcation complexes We thank Frantisek Baluska for helpful discussions during the preparation of this manuscript and Allison Piguet for proofreading the manuscript. This work was supported by the Swiss National Science Foundation grant No 3345-67200.01, Leenaards Foundation, NCCR oncology and the Geneva Cancer League to VP. VP is the recipient of a "Professor SNF*' position (PPOOA-68785).