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.

Structurally silent peptide anchor modifications allosterically modulate T cell recognition in a receptor-dependent manner

“…In some cases where anchor sensitivity has been observed, mechanistic detail has been provided and relates to how TCRs might differentially sense peptide motion or trigger peptide conformational changes (13,16,17). However, deeper insight into how anchor modifications alter peptide/MHC properties and how different TCRs perceive them is warranted, as careful peptide modification may still be a viable strategy for selectively improving immune responses in cancer and infectious disease (11,18,19). Moreover, the impact of peptide anchor modification is of heightened interest in the identification of immunologically active neoantigens.…”

Proinflammatory isoforms of IL-32 as novel and robust biomarkers for control failure in HIV-infected slow progressors

“…These subjects represent the HIV-infected slow progressors (SP), including the rare Elite Controller (EC) subgroup, which constitutes less than 1% of the HIV-infected population 10 11 . The low rate of transmission and slow disease progression associated with lower levels of HIV-RNA and prolonged high CD4 + T-cell counts make the study of these SP subjects of particular interest to inform and fuel potential strategies that support a functional cure for HIV infection 12 13 14 . Genome-wide association studies have implicated the major histocompatibility complex (MHC) class I region in natural control of HIV viral load (VL) 15 .…”

Natural heteroclitic-like peptides are generated by SARS-CoV-2 mutations

“…Interestingly, however, ~30% of the variant epitopes outperformed the CD8 reactivity of the corresponding prototype epitopes or elicited immune responses that were otherwise undetectable with prototype non-mutated epitopes, thus behaving as naturally evolved heteroclitic peptides. Heteroclitic peptides are typically created artificially, to induce stronger T cell responses by changing specific HLA anchor residues in order to increase HLA binding affinity or to generate new HLA anchor motifs, but also by modifying TCR binding residues in order to increase the affinity of peptide-HLA recognition by TCRs [43][44][45][46] . SARS-CoV-2 mutations within epitopic or flanking sequences able to mediate a more robust stimulation of CD8 T cell responses than their wild-type counterparts have occasionally been reported but never investigated in detail [47][48][49][50] .…”

“…Heteroclitic peptides are typically created artificially, to induce stronger T cell responses by changing specific HLA anchor residues in order to increase HLA binding affinity or to generate new HLA anchor motifs, but also by modifying TCR binding residues in order to increase the affinity of peptide-HLA recognition by TCRs 43–46 . SARS-CoV-2 mutations within epitopic or flanking sequences able to mediate a more robust stimulation of CD8 T cell responses than their wild-type counterparts have occasionally been reported but never investigated in detail 47–50 .…”