Mechanisms of viral transmission

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Mechanisms of viral transmission

• Classical route
• Infection in trans
• Cell to cell transmission

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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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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.

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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.

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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.

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Virological Synapse (VS)

• Synapse - point of contact
• Examples
• Neural synapse
• Immunological synapse
• Virological synapse

http//www.mult-sclerosis.org/synapse.html
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Synapses

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

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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.

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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.

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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.

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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.

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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.

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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 individuals
  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.

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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.

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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.

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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!

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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!

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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
  locationviral transport?

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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?

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Future questions

• Molecular basis of VS assembly?
• Where is HIV-1 stored within cells and why isnt
  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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