Enhancing Human Immunodeficiency Virus-Specific CD8(+) T Cell Responses with Heteroclitic Peptides

Abstract

Human immunodeficiency virus (HIV)-specific CD8(+) T cells play a critical role in containing HIV replication and delaying disease progression. However, HIV-specific CD8(+) T cells become progressively more "exhausted" as chronic HIV infection proceeds. Symptoms of T cell exhaustion range from expression of inhibitory receptors and selective loss of cytokine production capacity through reduced proliferative potential, impaired differentiation into effector cells and increased susceptibility to apoptosis. While effective combination antiretroviral therapy (cART) durably reduces HIV viremia to undetectable levels, this alone does not restore the full pluripotency of HIV-specific CD8(+) T cells. In a number of studies, a subset of peptide epitope variants categorized as heteroclitic, restimulated more potent cellular immune responses in vitro than did the native, immunizing peptides themselves. This property of heteroclitic peptides has been exploited in experimental cancer and chronic viral infection models to promote clearance of transformed cells and persistent viruses. In this review, we consider the possibility that heteroclitic peptides could improve the efficacy of therapeutic vaccines as part of HIV immunotherapy or eradication strategies. We review literature on heteroclitic peptides and illustrate their potential to beneficially modulate the nature of HIV-specific T cell responses toward those found in the small minority of HIV-infected, aviremic cART-naïve persons termed elite controllers or long-term non-progressors. Our review suggests that the efficacy of HIV vaccines could be improved by identification, testing, and incorporation of heteroclitic variants of native HIV peptide epitopes.

Keywords: CD8+ T cell; HIV; epitope; heteroclitic peptide; therapeutic vaccines.

Figure 1

Differential activation of HIV-specific CD8⁺ T cells by native and heteroclitic peptides. (A) HIV-specific CD8⁺ T cell stimulation with HIV-1 native peptide epitopes increases PD-1 expression. PD-1 ligation with its ligand (PD-L) causes immediate phosphorylation of the immunoreceptor tyrosine-based inhibitory motifs (ITIM) and immunoreceptor tyrosine-based switch motifs (ITSM). Recruitment of SHP-2 to the tyrosine residues associated with PD-1 dephosphorylates TCR ζ chains, downregulates TCR signaling, and prevents the phosphorylation of ZAP-70. (B) Heteroclitic peptide stimulation increases tyrosine phosphorylation of ZAP-70 and TCR ζ chains, and also downregulates PD-1 expression on responding T cells (downregulated PD-1 is shown in dotted lines). Signals generated by heteroclitic peptide stimulation through the TCR somehow bypass the PD-1 signaling pathway; thereby improving T cell responses. (C) Heteroclitic peptide stimulation selectively activates a different subset of HIV-specific CD8⁺ T cells that express less PD-1 than the CD8⁺ T cells responding to the native peptide.