STING Ligand-Mediated Priming of Functional CD8⁺T Cells Specific for HIV-1-Protective Epitopes from Naive T Cells

Abstract

Functional HIV-1-specific CD8 + T-cells primed from naïve T-cells are expected to act as effector T-cells in a ‘‘shock and kill’’ therapeutic strategy for an HIV-1 cure since less functional HIV-1-specific CD8 + T-cells are elicited from memory T-cells in HIV-1-infected individuals on cART. CD8 + T-cells specific for HIV-1 conserved and protective epitopes are candidates of such T-cells. We here investigated the priming with STING ligand of CD8 + T-cells specific for HLA-B*52:01 or HLA-C*12:02-restricted protective epitopes from naïve T-cells. STING ligand 3’3’-cGAMP effectively primed CD8 + T-cells specific for 3 of 4 HLA-B*52:01-restricted epitopes but failed to prime those specific for all 3 HLA-C*12:02-restricted epitopes from the naïve T-cells of HIV-1-uninfected individuals having an HLA-B*52:01-C*12:02 protective haplotype. These HLA-B*52:01-restricted CD8 + T-cells had a strong ability to suppress HIV-1 replication and expressed a high level of cytolytic effector molecules. The viral suppression ability of these T-cells was significantly correlated with the expression level of perforin and showed a trend for a positive correlation with the expression level of CD107a. The present study highlighted the priming with STING ligand of functional CD8 + T-cells specific for protective epitopes, which T-cells would contribute as effector T-cells to a ‘‘shock and kill’’ therapy. Importance Current therapeutic strategy ‘‘shock and kill’’ for HIV cure has been directed towards eliminating latent viral reservoirs by reactivation of latent reservoirs with latency-reversing agents followed by eradication of these cells by immune-mediated responses. Although HIV-1-specific T-cells are expected to eradicate viral reservoirs, the function of these T-cells is reduced in HIV-1-infected individuals with long-term cART. Therefore, priming of HIV-1-specific T-cells with high function from naïve T-cells are to be expected in these individuals. We here demonstrated the priming with STING ligand 3’3’-cGAMP of CD8 + T-cells specific for HIV-1 protective epitopes from naïve T cells. cGAMP primed CD8 + T-cells specific for 3 HLA-B*52:01-restricted protective epitopes, which cells expressed a high level of cytolytic effector molecules and effectively suppressed HIV-1 replication. The present study suggested that the priming with STING ligand of functional CD8 + T-cells specific for protective epitopes would be useful in a therapy for an HIV-1 cure.

HIV-1 protective epitope-specific CD8+ T cells in HIV-1-exposed seronegative individuals

“…The protein level of HLA alleles on HIV-1 infected cells is a critical factor for T cell priming. 52 Because the expressions of HLA-A and HLA-B were higher than that of HLA-C, 53 , 54 , 55 even in HIV-1-infected cells, HLA-A- or HLA-B-restricted T cells may be primed more immediately and effectively after exposure to HIV-1 than HLA-C-restricted T cells. Indeed, the number of reported HLA-C-restricted HIV-1 epitopes is much smaller than that of HLA-A-restricted or HLA-C-restricted epitopes (LANL-HSD: www.hiv.lanl.gov ).…”

“…In addition, a recent study of HIV-1-specific T cell priming from naive T cells demonstrated that HLA-B-restricted T cells were primed from naive T cells whereas HLA-C-restricted ones were not in the same individuals. 55 Other studies demonstrated that the peptide binding affinity was positively associated with the frequency of T cell responses in HIV-1-infected individuals 56 and that peptide stability may mediate T cell immunodominance. 57 These studies suggest that HIV-1-specific T cells are preferentially induced after exposure to HIV-1 in HESN individuals if the binding affinity and/or stability of the epitope peptide is high.…”