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HIV and the virological synapse
Quentin Sattentau
The Sir William Dunn School of Pathology University of Oxford
The talk
1. The HIV-1 T cell virological synapse
2. HIV-1-Macrophage-T cell interactions
HIV-1 sexual transmission
lumen epithelium
DC
lamina propria
Mac
T
GALT
T
TT
TT
T
T
hours days weeks
The traditional paradigm of enveloped virus infection
HIV-1 cycle ~24 hours
Cell-cell spread of HIV-1 is more efficient than cell-free
Cell polarisation and synapses
Hypothesis: The virological synapse (Jolly and Sattentau 2002)
Immunological synapse
The HIV-1 T cell-T cell synapse
CD3 LFA-1
Env
CD4 CXCR4
Env
Mergetarget
effector
Jolly et al JEM 2004
Polarization of CD4+ T cell secretion at the virological synapse
Jolly and Welsch unpublished
Architecture of the virological synapse
2F5
2G12
PRO T20Q41
20 B12 TAKD1D
2-IgP
0.00001
0.0001
0.001
0.01
0.1
1
10
100
Inhibitors
IC50
( μM
)
Cell-cellCell-free
Martin et al JVI 2010
The synapse family
PRE-SYNAPTIC
Neural Immunological Virological
POST-SYNAPTIC
PRE-SYNAPTIC
Macrophages, T cells and HIV
HIV infection of macrophages
Macrophages are infected early, live long, and become ‘viral reservoirs’
Infected macrophages contribute to viral pathogenesis in the mucosae and brain
But how are macrophages infected?
Macrophage uptake of HIV-1+ T cells
HIV-1-GFP
Macrophage uptake of HIV-1+ T cells bymultispectral flowcytometry(Imagestream™)
CD3 = T cell
Gag p24 = HIV-1
Caspase-3 = apoptosis
Viral escape from degradation?
Macrophage engulfement ofHIV+ T cells
Welsch unpublished
Macrophage – virus compartment
Env
Gag
Welsch et al JVI 2011
Macrophage - T cell synapse
CD4
Gag Groot et al Blood 2008
Working model for macrophage-T cell HIV-1 infection
Mφ T
T
Synapse
PhagocytosisT
Acknowledgements
OxfordFedde GrootBecky RussellAmy BaxterChris DuncanMike ShawChris WillbergClair JollyIvonne Mitar
HeidelbergSonja WelschJohn Briggs
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