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Jolly and Welsch unpublished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Welsch unpublished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