Smarter vaccine design will circumvent regulatory T cell-mediated evasion in chronic HIV and HCV infection

Abstract

Despite years of research, vaccines against HIV and HCV are not yet available, due largely to effective viral immunoevasive mechanisms. A novel escape mechanism observed in viruses that cause chronic infection is suppression of viral-specific effector CD4(+) and CD8(+) T cells by stimulating regulatory T cells (Tregs) educated on host sequences during tolerance induction. Viral class II MHC epitopes that share a T cell receptor (TCR)-face with host epitopes may activate Tregs capable of suppressing protective responses. We designed an immunoinformatic algorithm, JanusMatrix, to identify such epitopes and discovered that among human-host viruses, chronic viruses appear more human-like than viruses that cause acute infection. Furthermore, an HCV epitope that activates Tregs in chronically infected patients, but not clearers, shares a TCR-face with numerous human sequences. To boost weak CD4(+) T cell responses associated with persistent infection, vaccines for HIV and HCV must circumvent potential Treg activation that can handicap efficacy. Epitope-driven approaches to vaccine design that involve careful consideration of the T cell subsets primed during immunization will advance HIV and HCV vaccine development.

Keywords: HCV; HIV; MHC class II; T cell epitope; cross-reactivity; immunoinformatics; regulatory T cells; vaccines.

FIGURE 1

Predicted Treg-activating HIV and HCV sequences possess TCR faces shared by numerous human proteins. Epitope networks are shown, illustrating the abundance of TCR faces one HCV and one HIV peptide share with the human genome as determined by JanusMatrix analysis. The HIV and HCV source peptides are represented by green diamonds, their constituent 9-mer epitopes by gray squares, their cross-conserved partners in the human genome by blue triangles, and the source human proteins by light purple circles. In the HIV peptide (right) a single cross-conserved epitope can be found in 32 different HLA class I alleles; several additional 9-mer epitopes are cross-conserved with 12 other HLA sequences (source protein orange highlight).