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Enhanced induction of HIV-specific CTL by dendritic cell-targeted delivery of SOCS-1 siRNA

Background

Dendritic cells (DC) are potent antigen-presenting cells that play a critical role in the activation of T cells. Antigen-loaded dendritic cell-based vaccines have been used for immunotherapy of human cancers and chronic infections, but only with limited success. RNAi-mediated silencing of negative immunoregulatory molecules expressed by DCs may provide a strategy to enhance the potency of DC-based vaccines and immunotherapy.

Methods

We have used a novel human HLA-A2 transgenic NOD/SCID-iL2rg chain -/- mice reconstituted with CD34+ HSC from A2 donors as a preclinical model to induce a robust CD8+ T cell-mediated protective immune response to HIV infection.

Results

SOCS-1 knockdown in human DCs a) enhanced their cytokine responses to LPS, and stimulated a strong mixed lymphocyte reaction in vitro, b) elicited a strong primary in vitro response to HLA-A2-restricted Melan-A/MART-1 and HIV Gag epitopes in naïve CD8+ T cells from healthy donors and c) increased the HIV gag-specific proliferation and polyfunctional cytokine response in CD8 T cells from seropositive subjects. More importantly, injection of gag peptide-pulsed, SOCS-1 silenced, but not just peptide pulsed HLA-A2 DCs, in the novel HLA-A2 humanized mice, gave rise to a robust multi-epitope-HIV specific CD8 T cells that could dramatically reduce the replication of a HIV-Gag-vaccinia recombinant challenge virus infection.

Discussion

These results demonstrate the feasibility of using manipulated DC as a prophylactic vaccine strategy for HIV infection in a humanized mouse model.

Author information

Correspondence to Sandesh Subramanya.

Rights and permissions

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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Keywords

  • Mixed Lymphocyte Reaction
  • Humanize Mouse
  • Humanize Mouse Model
  • Seropositive Subject
  • Immunoregulatory Molecule