The inability to disrupt the immunological synapse between infected human T cells and APCs distinguishes HIV-1 from most other primate lentiviruses
Nathalie Arhel, … , Vincent Piguet, Frank Kirchhoff
Nathalie Arhel, … , Vincent Piguet, Frank Kirchhoff
Published September 14, 2009
Citation Information: J Clin Invest. 2009;119(10):2965-2975. https://doi.org/10.1172/JCI38994.
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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

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Figure 3

Nef-mediated downmodulation of TCR-CD3 prevents Lck polarization at the IS.

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Nef-mediated downmodulation of TCR-CD3 prevents Lck polarization at the ...
(A) CD4+ T cells infected with HIV-1 constructs expressing the indicated nef alleles were incubated with autologous sAg-pulsed DCs, fixed, and stained with anti-Lck. Images show representative confocal acquisitions from cocultures between infected CD4+ T cells and autologous sAg-pulsed DCs labeled with DAPI. Shown are Lck Ab labeling alone and merged images of eGFP, DAPI, and Lck. Arrowheads point to zones of close contact between infected T cells and DCs. Scale bars: 5 μm. (B) Number of HIV-1–infected eGFP+ T cells engaged in complex formation with APCs, showing accumulation of Lck at the IS. Results are mean ± SD of 2 independent experiments. *P < 0.05; ***P < 0.001.