Effects of Cross-Presentation, Antigen Processing, and Peptide Binding in HIV Evasion of T Cell Immunity

J Immunol. 2018 Mar 1;200(5):1853-1864. doi: 10.4049/jimmunol.1701523. Epub 2018 Jan 26.


Unlike cytosolic processing and presentation of viral Ags by virus-infected cells, Ags first expressed in infected nonprofessional APCs, such as CD4+ T cells in the case of HIV, are taken up by dendritic cells and cross-presented. This generally requires entry through the endocytic pathway, where endosomal proteases have first access for processing. Thus, understanding virus escape during cross-presentation requires an understanding of resistance to endosomal proteases, such as cathepsin S (CatS). We have modified HIV-1MN gp120 by mutating a key CatS cleavage site (Thr322Thr323) in the V3 loop of the immunodominant epitope IGPGRAFYTT to IGPGRAFYVV to prevent digestion. We found this mutation to facilitate cross-presentation and provide evidence from MHC binding and X-ray crystallographic structural studies that this results from preservation of the epitope rather than an increased epitope affinity for the MHC class I molecule. In contrast, when the protein is expressed by a vaccinia virus in the cytosol, the wild-type protein is immunogenic without this mutation. These proof-of-concept results show that a virus like HIV, infecting predominantly nonprofessional presenting cells, can escape T cell recognition by incorporating a CatS cleavage site that leads to destruction of an immunodominant epitope when the Ag undergoes endosomal cross-presentation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigen Presentation / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • Cathepsins / immunology
  • Cross-Priming / immunology*
  • Dendritic Cells / immunology
  • Epitopes, T-Lymphocyte / immunology
  • HEK293 Cells
  • HIV / immunology*
  • HIV Envelope Protein gp120 / immunology
  • HIV Infections / immunology*
  • Histocompatibility Antigens Class I / immunology
  • Humans
  • Immune Evasion / immunology*
  • Immunodominant Epitopes / immunology
  • Mice
  • Mice, Inbred BALB C
  • Peptides / immunology*
  • Vaccinia virus / immunology


  • Epitopes, T-Lymphocyte
  • HIV Envelope Protein gp120
  • Histocompatibility Antigens Class I
  • Immunodominant Epitopes
  • Peptides
  • Cathepsins
  • cathepsin S