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 October 1, 2009; First 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 1

Nef alleles that downmodulate TCR-CD3 impair the ability of virally infected primary T cells to form complexes with APCs.

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Nef alleles that downmodulate TCR-CD3 impair the ability of virally inf...
(A and B) PBLs were infected with NL4-3–IRES–eGFP viruses encoding different Nefs, and complex formation with autologous SEE-pulsed DCs and MDMs was assessed 4 days after infection by fluorescence microscopy (A) and flow cytometry (B). (A) Representative acquisition frames of cocultures between infected PBLs and MDMs or DCs, with phase-contrast (Nomarski), eGFP, and PKH26 superimposed. Scale bars: 10 μm. The proportion of infected (eGFP+) cells contacting labeled autologous MDMs or DCs was scored randomly by single-blind method with n = 60 per sample per experiment. Results are mean ± SD of 4–5 independent experiments. In all experiments, 25%–55% of PBLs infected with the nef-defective control HIV-1 construct (nef–) formed complexes with autologous APCs; nef– values are set as 100%. (B) Representative flow cytometry acquisitions for complex formation between infected PBLs and MDMs or DCs. Percentages denote the number of eGFP+ cells in the DC gating that are PKH26+ (as a percentage of all eGFP+ cells). Graphs show mean ± SD of 3 and 4 experiments in DCs and MDMs, respectively. In all experiments, 3%–13% of PBLs infected with nef– formed complexes with autologous APCs; nef– values are set as 100%. Red and green bars denote nef alleles of group 1 and group 2, respectively. Combined results for group 1 (G1) and group 2 (G2) Nefs represent average values ± SD. *P < 0.05; #P < 0.01; §P < 0.001.