Date Published: September 12, 2017
Publisher: BioMed Central
Author(s): Kayla A. Holder, Michael D. Grant.
Chronic infection with human immunodeficiency virus (HIV) causes HIV-specific CD8+ T cell dysfunction and exhaustion. The strong association between non-progression and maintenance of HIV-specific CD8+ T cell cytokine production and proliferative capacities suggests that invigorating CD8+ T cell immune responses would reduce viremia and slow disease progression. A series of studies have demonstrated that sequence variants of native immunogenic peptides can generate more robust CD8+ T cell responses and that stimulation with these ‘heteroclitic’ peptides can steer responses away from the phenotypic and functional attributes of exhaustion acquired during chronic HIV infection. Incorporation of heteroclitic peptide stimulation within therapeutic vaccines could favour induction of more effective cellular antiviral responses, and in combination with ‘shock and kill’ strategies, contribute towards HIV cure.
Cytotoxic CD8+ T cells kill damaged, malignant or virus-infected cells through granule-relayed or receptor-mediated mechanisms. Recognition by, and activation of CD8+ T cells is governed via interaction between the T cell receptor (TCR) and antigen-derived peptides bound within cognate class I major histocompatibility complexes (MHC-I). Stabilizing derivations that fasten antigenic peptides to MHC (pMHC) molecules more securely, or enhance TCR binding to the pMHC complex, increase peptide immunogenicity [1, 2].
Methods of augmenting TCR:pMHC complex avidity are varied and can involve either modifying the TCR or MHC-I complexes themselves, or creating peptide sequence variants [1, 2]. Augmenting T cell responses and effector functions via the latter method offers a less invasive and simpler approach to CD8+ T cell-based HIV vaccine therapy. As individual T cell clones recognize series’ of related peptides, constructing heteroclitic sequence variants that increase TCR:pMHC avidity, relative to reference peptides, can produce more potent CD8+ T cell responses . Solinger et al. demonstrated the phenomenon of heteroclitic peptides as murine T cells primed with pigeon cytochrome c proliferated to a greater extent following restimulation with moth cytochrome c than with pigeon cytochrome c . Mapping the T cell response to the immunodominant portion of the antigen affirmed that one family of clones can react equally well to either the priming peptide itself or to variant peptides encompassing amino acid (aa) substitutions, and that conservative modifications can support enhanced binding to MHC proteins or strengthen TCR:pMHC interactions .
Cytotoxic CD8+ T cells (CTL) are critical for controlling certain cancers, HIV and many other viral infections . They predominantly eliminate infected cells through production and targeted release of cytotoxins . Studies of HIV slow or non-progressors demonstrated strong cellular immune responses against HIV in association with class I human histocompatibility-linked leukocyte antigen (HLA) B*57 alleles . Long-term non-progressors mount especially robust CD8+ T cell responses against HLA B*57-restricted HIV Gag protein peptide epitopes . As CTL activity is maintained in chronic HIV infection with selective peptide stimulation in this genetically restricted context, identifying variant peptides that can efficiently induce and maintain CTL activity during progressive HIV infection across a broader genetic background could be an effective therapeutic vaccine strategy. In this context, several anchor-modified variants of the HIV reverse transcriptase (RT) peptide (ILKEPVHGV) enabled greater HIV-specific CD8+ T cell cytotoxic responses than stimulation with reference peptide [15, 16].
Synthetic peptide variants can enhance MHC interaction with the TCR by reducing adverse interactions or by increasing favourable ones. Consequently, variant peptides have a significantly better capacity to boost weak immune responses than their naturally occurring counterparts. Amino acid substitutions within defined HIV epitopes, such as those within genes encoding structural (gag) or enzymatic (pol) proteins, stimulate stronger immune responses . With a lower mutation rate than the env gene, choosing epitopes from gag- or pol–derived HLA-restricted immunodominant proteins would provide optimal and prolonged CD8+ T cell responses . Though poorly immunogenic on their own, delivering heteroclitic peptides in combination with a monophosphoryl lipid A (MPA) and alum formulation or oil-based adjuvant will stimulate the host immune system and trigger a response favouring cytotoxicity . Incorporating heteroclitic peptides in HIV therapeutic vaccination strategies has the potential, in ways that native peptide vaccines lack, to invigorate HIV-specific CD8+ T cell responses, thwart T cell exhaustion and reduce viremia in cases of disease progression.