No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target....
Transcript of No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target....
![Page 1: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/1.jpg)
HIV and the virological synapse
Quentin Sattentau
The Sir William Dunn School of Pathology University of Oxford
![Page 2: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/2.jpg)
The talk
1. The HIV-1 T cell virological synapse
2. HIV-1-Macrophage-T cell interactions
![Page 3: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/3.jpg)
HIV-1 sexual transmission
lumen epithelium
DC
lamina propria
Mac
T
GALT
T
TT
TT
T
T
hours days weeks
![Page 4: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/4.jpg)
The traditional paradigm of enveloped virus infection
HIV-1 cycle ~24 hours
![Page 5: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/5.jpg)
Cell-cell spread of HIV-1 is more efficient than cell-free
![Page 6: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/6.jpg)
Cell polarisation and synapses
Hypothesis: The virological synapse (Jolly and Sattentau 2002)
Immunological synapse
![Page 7: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/7.jpg)
The HIV-1 T cell-T cell synapse
CD3 LFA-1
Env
CD4 CXCR4
Env
Mergetarget
effector
Jolly et al JEM 2004
![Page 8: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/8.jpg)
Polarization of CD4+ T cell secretion at the virological synapse
Jolly and Welsch unpublished
![Page 9: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/9.jpg)
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
![Page 10: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/10.jpg)
The synapse family
PRE-SYNAPTIC
Neural Immunological Virological
POST-SYNAPTIC
PRE-SYNAPTIC
![Page 11: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/11.jpg)
Macrophages, T cells and HIV
![Page 12: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/12.jpg)
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?
![Page 13: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/13.jpg)
Macrophage uptake of HIV-1+ T cells
HIV-1-GFP
![Page 14: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/14.jpg)
Macrophage uptake of HIV-1+ T cells bymultispectral flowcytometry(Imagestream™)
CD3 = T cell
Gag p24 = HIV-1
Caspase-3 = apoptosis
![Page 15: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/15.jpg)
Viral escape from degradation?
![Page 16: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/16.jpg)
Macrophage engulfement ofHIV+ T cells
Welsch unpublished
![Page 17: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/17.jpg)
Macrophage – virus compartment
Env
Gag
Welsch et al JVI 2011
![Page 18: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/18.jpg)
Macrophage - T cell synapse
CD4
Gag Groot et al Blood 2008
![Page 19: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/19.jpg)
Working model for macrophage-T cell HIV-1 infection
Mφ T
T
Synapse
PhagocytosisT
![Page 20: No Slide Title · The HIV-1 T cell-T cell synapse CD3 LFA-1. Env. CD4. CXCR4. Env. Merge. target. effector. Jolly et al JEM 2004](https://reader034.fdocuments.net/reader034/viewer/2022042321/5f0b7eea7e708231d430cdba/html5/thumbnails/20.jpg)
Acknowledgements
OxfordFedde GrootBecky RussellAmy BaxterChris DuncanMike ShawChris WillbergClair JollyIvonne Mitar
HeidelbergSonja WelschJohn Briggs