Design and evaluation of optimized artificial HIV-1 poly-T cell-epitope immunogens

PLoS One. 2015 Mar 18;10(3):e0116412. doi: 10.1371/journal.pone.0116412. eCollection 2015.

Abstract

A successful HIV vaccine in addition to induction of antibody responses should elicit effective T cell responses. Here we described possible strategies for rational design of T-cell vaccine capable to induce high levels of both CD4+ and CD8+ T- cell responses. We developed artificial HIV-1 polyepitope T-cell immunogens based on the conserved natural CD8+ and CD4+ T cell epitopes from different HIV-1 strains and restricted by the most frequent major human leukocyte antigen (HLA) alleles. Designed immunogens contain optimized core polyepitope sequence and additional "signal" sequences which increase epitope processing and presentation to CD8+ and CD4+ T-lymphocytes: N-terminal ubiquitin, N-terminal signal peptide and C-terminal tyrosine motif of LAMP-1 protein. As a result we engineered three T cell immunogens - TCI-N, TCI-N2, and TCI-N3, with different combinations of signal sequences. All designed immunogens were able to elicit HIV-specific CD4+ and CD8+ T cell responses following immunization. Attachment of either ubiquitin or ER-signal/LAMP-1 sequences increased both CD4+ and CD8+ mediated HIV-specific T cell responses in comparison with polyepitope immunogen without any additional signal sequences. Moreover, TCI-N3 polyepitope immunogen with ubiquitin generated highest magnitude of HIV-specific CD4+ and CD8+ T cell responses in our study. Obtained data suggests that attachment of signal sequences targeting polyepitope immunogens to either MHC class I or MHC class II presentation pathways may improve immunogenicity of T-cell vaccines. These results support the strategy of the rational T cell immunogen design and contribute to the development of effective HIV-1 vaccine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AIDS Vaccines / genetics
  • AIDS Vaccines / immunology*
  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Epitopes, T-Lymphocyte / genetics
  • Epitopes, T-Lymphocyte / immunology*
  • Female
  • HEK293 Cells
  • HIV-1 / genetics
  • HIV-1 / immunology*
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class II / immunology
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Vaccines, Synthetic / genetics
  • Vaccines, Synthetic / immunology

Substances

  • AIDS Vaccines
  • Epitopes, T-Lymphocyte
  • Histocompatibility Antigens Class I
  • Histocompatibility Antigens Class II
  • Vaccines, Synthetic

Grants and funding

The part of work concerning immunogens design and DNA vaccine construction was supported by grant 12-04-00857-a from Russian Foundation for Basic Research (www.rfbr.ru). The study of the HIV-specific immune response and data analysis were supported by Russian Science Foundation grant 14-14-00660 (www.rscf.ru).