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Mechanisms of viral transmission

Mechanisms of viral transmission. Classical route Infection in trans Cell to cell transmission. Viral Transmission. Classical route: Cell free virions bind to permissive host cell with receptor-ligand interactions, followed by fusion to enter the cytoplasm and then replicative events.

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Mechanisms of viral transmission

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  1. Mechanisms of viral transmission • Classical route • Infection in trans • Cell to cell transmission

  2. Viral Transmission • Classical route: • Cell free virions bind to permissive host cell with receptor-ligand interactions, followed by fusion to enter the cytoplasm and then replicative events.

  3. Viral Transmission • Infection in trans: • Dendritic cells capture virus that binds to C-type lectins (or other cell surface receptors), without necessarily becoming actively infected, and present infectious virus to permissive target cells.

  4. Viral Transmission • Cell to cell transmission: • An actively infected cell can directly infect a second cell, without requirement for releasing cell-free virions into the local environment.

  5. Why is cell to cell transmission advantageous? • Bypasses the need for virus diffusion into the local enviroment. • Minimizes exposure to viral neutralization defenses such as antibodies and complement.

  6. Virological Synapse (VS) • Synapse - ‘point of contact’ • Examples: • Neural synapse • Immunological synapse • Virological synapse http://www.mult-sclerosis.org/synapse.html

  7. Synapses • Neural synapse: • Points of contiguity between neurons, across which information is relayed via neurotransmitters. • Stability is established with adhesion molecules, mainly cadherins.

  8. Synapses • Immunological synapse: • All intercellular junctions that provide a stable environment for immunological events such as signaling via receptor engagement and directed secretion of cytokines, lytic granules, etc. • Rapid assembly, disassembly required, for interaction with multiple target cells.

  9. Synapses • Virological synapse: • Cells contact each other but do not fuse. • A stable, adhesive junction forms. • Secretion of viral material across the synapse is directed by cellular machinery.

  10. Viruses studied • Human immunodeficiency virus (HIV-1) • Human T cell leukemia virus (HTLV-1) • Similar mechanisms may involve other viruses including SARS, Ebola, Dengue, SIV, etc.

  11. Cell-free viral spread is inefficient • HTLV-1: • Spread between and within individuals by cell to cell transfer from infected T cells. • This may explain why CD4 T cells are the main target in vivo, even though HTLV-1 receptors are ubiquitous on mammalian cells.

  12. Virological synapses • HIV-1: • Dendritic Cell (DC) - T cell • T cell - T cell • SARS: • Similar mechanisms? • SARS-Corona virus pseudotyped lentiviral vector was transferred from DC to target cell through HIV-1-like virological synapse.

  13. 3 HIV-1 transmission routes • Dendritic cell captures cell-free virions at the mucosa by interaction between cell surface lectins (DC-SIGN) and the HIV-1 envelope protein (Env). • Infected T cell enters an uninfected individual’s mucosa, allowing spread of virion to permissive cells including macrophages and epithelial cells. • Infected T cell engages an epithelial cell and transcytoses virus across the epithelial cell to underlying tissue without epithelial infection.

  14. Dendritic cells • Langerhans cells • Myeloid dermal dendritic cells • Before pathogen exposure: • In skin and mucosa in an immature resting state. • After pathogen exposure: • DCs mature and migrate from peripheral tissues to lymphoid organs to initiate immune responses.

  15. DC-SIGN • C-type lectin = CD209. • Highly expressed on immature DCs. • Attachment factor for many viruses. • HIV-1 taken up by DC-SIGN remains infectious in separate intracellular compartments.

  16. Double edged sword • Both HIV-infected DCs and uninfected DCs presenting virus can cause robust infections in vitro. • DC-T cell interactions initiated by the host to generate immune responses may also provide a suitable microenvironment for viral spread!

  17. VS Events • T cell scanning - non-specific transient DC-T cell contacts for potential peptide recognition. • HIV-infected DCs have concentrated virion at VS, and T cell receptors are recruited to VS… Efficient transmission!

  18. VS Details • HIV Env protein on effector cell binds CD4 and CXCR4 on naïve T cells to activate recruitment of viral receptors and LFA-1 at VS. • LFA-1 may bind ICAMs to provide VS stability. • Microtubule organizing center (MTOC) reorients in the infected cell in relation to VS location…viral transport?

  19. Virological vs Immunologic Synapses • Similarities: initial adhesion interactions. • Differences: In subsequent reactions, IS uses pSMAC, cSMAC for stability and secretion. • Cellular machinery for immunological synapses (IS) has evolved to benefit the the host… do viruses just harness that machinery for their own use, or do they modify and use other paths?

  20. Future questions • Molecular basis of VS assembly? • Where is HIV-1 stored within cells and why isn’t it degraded? • What triggers movement of the virus-containing compartment to the VS? • How important is VS to HIV transmission in vivo and involving other cell types?

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