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Volume 6 Supplement 3

AIDS Vaccine 2009

P09-03. HLA class I alleles impact on HIV-1 disease progression by interacting with immunoregulatory HLA receptors on dendritic cells

Background

HLA-B*35-Px subtypes are associated with accelerated HIV-1 disease courses, in contrast to HLA-B*35-PY subtypes which do not have any detectable impact on HIV-1 disease, although they differ in as few as one amino acid. The mechanisms accounting for the differential influence of HLA-B*35 subtypes on HIV-1 disease progression remain unclear. ILT4 is an inhibitory HLA class I receptor that is upregulated during HIV-1 infection and can critically regulate the functional profile of DCs.

Methods

To test whether HIV-1 CTL epitopes presented by alternative HLA-B*35 subtypes are differentially recognized by ILT4, we used recombinant HLA-B*3501 (PY) and -B*3503 (Px) tetramers refolded with two dominant B*35-restricted epitopes to stain mDC from HIV-1 infected individuals. Functional consequences of the altered recognition of these tetramers by ILT4 were performed using mix lymphocyte reaction.

Results

HLA-B*3503 complexes had significantly higher (p = 0.01) ILT4-mediated binding intensities to mDC, compared to the respective p/B*3501 complexes refolded with identical epitopes. Biacore experiments confirmed a significantly higher binding affinity between recombinant ILT4 and HLA-B35-Px molecules compared to HLA-B35-PY molecules. Higher recognition of the B*35-Px complexes by ILT4 led to DC dysfunction and significantly impaired the proliferation of allogeneic T cells (p = 0.0027) compared to B*35-PY tetramers; this effect could be reversed by si-RNA-mediated ILT4 knockdown. Ex vivo MLR assays showed that mDCs isolated from HIV-1 infected carriers of HLA-B*35-Px had a significantly weaker capacity for allogeneic T cell expansion compared to DCs from B*35-PY carriers (p = 0.002).

Conclusion

Inhibitory impulses resulting from preferential recognition of B*35-Px subtypes by ILT4 and subsequent DC dysfunction might contribute to the accelerated HIV-1 disease progression associated with HLA-B*35-Px subtypes. Differential interactions between HLA class I alleles and immunoregulatory MHC class I receptors on DCs provide a novel perspective for the understanding of how MHC class I impact HIV-1 disease progression.

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Correspondence to J Huang.

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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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Huang, J. P09-03. HLA class I alleles impact on HIV-1 disease progression by interacting with immunoregulatory HLA receptors on dendritic cells. Retrovirology 6, P116 (2009). https://doi.org/10.1186/1742-4690-6-S3-P116

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Keywords

  • Identical Epitope
  • Inhibitory Impulse
  • Preferential Recognition
  • Infected Carrier
  • Biacore Experiment