Transcript Wk8 - ViralSyn

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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!
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!
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?
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?
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 viruscontaining compartment to the VS?
• How important is VS to HIV transmission in
vivo and involving other cell types?
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