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Volume 6 Supplement 3

AIDS Vaccine 2009

P16-08. Combined blockade of the PD-1 and IL-10 pathways synergistically enhance HIV-specific CD4 T cell functions

Background

HIV-specific T cell dysfunction is a prominent feature of HIV infection. We have reported that the PD-1 and IL-10 pathways mediate a reversible impairment of HIV-specific proliferative T cell responses. However, the responses are frequently modest and not all infected subjects respond to blockade of either pathway. It is therefore crucial to determine whether combined PD-L1 and IL-10Rα blockade can overcome these limitations and synergistically revive HIV-specific T cell responses.

Methods

We investigated 17 persons with HIV infection that were divided into groups according to treatment status. We used Luminex arrays to measure IFN-γ and IL-2 secretion in supernatants of CD8-depleted PBMC stimulated for 48 h with a Gag peptide pool or left unstimulated in the presence of isotype control antibody, anti-PD-L1, anti-IL-10Rα or combined blockade.

Results

In viremic individuals (n = 10), blockade of a single or two inhibitory pathways resulted in a significant increase in IFNγ secretion by HIV-specific CD4 T cells when compared to the isotype control condition (p < 0.0001, Friedman test with Dunn's post-test). The median fold-increase in IFN-γ secretion was 1.8 for PD-L1, 5.1 for IL-10Rα and 13.4 for combined blockade. In subjects with higher viral loads, combined PD-L1/IL-10Rα blockade resulted in an occasionally dramatic synergistic effect, even when a limited increase was seen with PD-L1 blockade alone. We also observed a non-significant trend toward increased IL-2 secretion upon inhibitory blockade. In contrast, in aviremic subjects, IL-10Rα blockade was not more effective than PD-L1 blockade, and additive effects of combined blockade were inconstant.

Conclusion

These data indicate that combined blockade of the PD-1 and IL-10 pathways synergize to restore effector functions of HIV specific CD4 T cells and demonstrate the potential of targeting multiple inhibitory pathways to reverse T cell exhaustion in humans. These results may have significant implications for development of novel immunotherapeutic interventions.

Author information

Correspondence to F Porichis.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Porichis, F., Kwon, D., Tighe, D. et al. P16-08. Combined blockade of the PD-1 and IL-10 pathways synergistically enhance HIV-specific CD4 T cell functions. Retrovirology 6, P237 (2009). https://doi.org/10.1186/1742-4690-6-S3-P237

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Keywords

  • Isotype Control
  • High Viral Load
  • Peptide Pool
  • Isotype Control Antibody
  • Cell Exhaustion