Novel approaches in polyepitope T-cell vaccine development against HIV-1

Abstract

RV144 clinical trial was modestly effective in preventing HIV infection. New alternative approaches are needed to design improved HIV-1 vaccines and their delivery strategies. One of these approaches is construction of synthetic polyepitope HIV-1 immunogen using protective T- and B-cell epitopes that can induce broadly neutralizing antibodies and responses of cytotoxic (CD8⁺ CTL) and helpers (CD4⁺ Th) T-lymphocytes. This approach seems to be promising for designing of new generation of vaccines against HIV-1, enables in theory to cope with HIV-1 antigenic variability, focuses immune responses on protective determinants and enables to exclude from the vaccine compound that can induce autoantibodies or antibodies enhancing HIV-1 infectivity. Herein, the authors will focus on construction and rational design of polyepitope T-cell HIV-1 immunogens and their delivery, including: advantages and disadvantages of existing T-cell epitope prediction methods; features of organization of polyepitope immunogens, which can generate high-level CD8⁺ and CD4⁺ T-lymphocyte responses; the strategies to optimize efficient processing, presentation and immunogenicity of polyepitope constructs; original software to design polyepitope immunogens; and delivery vectors as well as mucosal strategies of vaccination. This new knowledge may bring us a one step closer to developing an effective T-cell vaccine against HIV-1, other chronic viral infections and cancer.

Keywords::

• CD4⁺ T-cells
• CD8⁺ T-cells
• HIV-1
• MHC class I molecules
• MHC class II molecules
• mucosal immunity
• polyepitope T-cell immunogen
• rational design
• vaccine
• vaccine delivery

Financial & competing interests disclosure

The reported study was partially supported by RFBR (research project No. 12-04-00857-a and 12-04-31746 mol_a) and by the Ministry of education and science of Russia, projects No 8278 and 8289). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Synthetic polyepitope HIV-1 immunogens comprise protective determinants and exclude antibody determinants that enhancing infectivity of HIV-1.

• Polyepitope T-cell construct must provide a high expression of gene encoding target immunogen, effective processing and presentation of released peptides to CD8⁺ T-lymphocytes.

• Optimal CD8⁺ T-cell vaccines must induce responses to variety of determinants restricted by different HLAs to cover genetic diversity of human population.

• Rational strategy to enhance immunogenicity is to maximize expression of MHC class I-peptide complexes on the surface of APC.

• Robust CD4⁺ T-helper response is critical in giving help to CD8 T-cells and to development of Env-specific neutralizing antibodies. For induction of CD4⁺ T-cell responses it is necessary to target antigen to lysosomal compartment for degradation and subsequent peptide binding to MHC class II molecules in order to stimulate response of CD4⁺ T-helper cells using LAMP.

• PolyCTLDesigner software is capable to carry out rational design of polyepitope T-cell antigens providing high level of CD8⁺ T-cell responses due to optimization of spacer sequences between epitopes and optimization of order of epitopes in polyepitope construct.

• Mucosal immunization with polyepitope T-cell vaccine has proven to be very effective for generation of local compartmentalized T- and B-cell immune responses and mucosal protection against viral infections, including SHIV.