The inability to disrupt the immunological synapse between infected human T cells and APCs distinguishes HIV-1 from most other primate lentiviruses
Nathalie Arhel, Martin Lehmann, Karen Clauß, G. Ulrich Nienhaus, Vincent Piguet, Frank Kirchhoff
Nathalie Arhel, Martin Lehmann, Karen Clauß, G. Ulrich Nienhaus, Vincent Piguet, Frank Kirchhoff
View: Text | PDF
Research Article Virology

The inability to disrupt the immunological synapse between infected human T cells and APCs distinguishes HIV-1 from most other primate lentiviruses

Abstract

Viruses that infect T cells, including those of the lentivirus genus, such as HIV-1, modulate the responsiveness of infected T cells to stimulation by interacting APCs in a manner that renders the T cells more permissive for viral replication. HIV-1 and other primate lentiviruses use their Nef proteins to manipulate the T cell/APC contact zone, the immunological synapse (IS). It is known that primate lentiviral Nef proteins differ substantially in their ability to modulate cell surface expression of the TCR-CD3 and CD28 receptors critical for the formation and function of the IS. However, the impact of these differences in Nef function on the interaction and communication between virally infected T cells and primary APCs has not been investigated. Here we have used primary human cells to show that Nef proteins encoded by HIV-2 and most SIVs, which downmodulate cell surface expression of TCR-CD3, disrupt formation of the IS between infected T cells and Ag-presenting macrophages or DCs. In contrast, nef alleles from HIV-1 and its simian precursor SIVcpz failed to suppress synapse formation and events downstream of TCR signaling. Our data suggest that most primate lentiviruses disrupt communication between virally infected CD4+ Th cells and APCs, whereas HIV-1 and its SIV precursor have largely lost this capability. The resulting differences in the levels of T cell activation and apoptosis may play a role in the pathogenesis of AIDS.

Authors

Nathalie Arhel, Martin Lehmann, Karen Clauß, G. Ulrich Nienhaus, Vincent Piguet, Frank Kirchhoff

×

Figure 5

Nef alleles that downmodulate TCR-CD3 impair CD43 exclusion at the IS.

Options: View larger image (or click on image) Download as PowerPoint
Nef alleles that downmodulate TCR-CD3 impair CD43 exclusion at the IS. I...
Images show representative confocal acquisitions from cocultures between infected PBLs and autologous SEE-pulsed DCs. Shown are CD43 Ab labeling alone and merged images of eGFP, PKH26, and CD43. Scale bars: 5 μm. Close contact was rarely observed in PBL/APC cultures infected with viral constructs expressing HIV-2 BEN or SIVblu Nefs, and occasional cell-cell complexes did not show CD43 exclusion, as determined by microscopic examination and analysis of the CD43 signal intensity along the plane of the cell-cell interface. The x axis represents distance along the contact zone; the y axis denotes pixel intensity. The location of 3–4 representative points per construct, and their corresponding intensities, are shown by the numbered arrowheads.