Cross-reactive microbial peptides can modulate HIV-specific CD8+ T cell responses.

Christopher W Pohlmeyer,Alison Livingston,Jennifer E Thorne,Sarah E Beck,John A Flynn,Nicholas J Butler,Richard D Moore,Caroline C Garliss,Joel N Blankson,Robert F Siliciano,Sarah B Laskey,Daniel C Xu,Walt Lichmira,Megan E May,M Sue Leffell,Adam A Capoferri,Derya Unutmaz

doi:10.1371/journal.pone.0192098

Christopher W Pohlmeyer, Alison Livingston + Show 15 more

Open Access

https://doi.org/10.1371/journal.pone.0192098

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Abstract

Heterologous immunity is an important aspect of the adaptive immune response. We hypothesized that this process could modulate the HIV-1-specific CD8+ T cell response, which has been shown to play an important role in HIV-1 immunity and control. We found that stimulation of peripheral blood mononuclear cells (PBMCs) from HIV-1-positive subjects with microbial peptides that were cross-reactive with immunodominant HIV-1 epitopes resulted in dramatic expansion of HIV-1-specific CD8+ T cells. Interestingly, the TCR repertoire of HIV-1-specific CD8+ T cells generated by ex vivo stimulation of PBMCs using HIV-1 peptide was different from that of cells stimulated with cross-reactive microbial peptides in some HIV-1-positive subjects. Despite these differences, CD8+ T cells stimulated with either HIV-1 or cross-reactive peptides effectively suppressed HIV-1 replication in autologous CD4+ T cells. These data suggest that exposure to cross-reactive microbial antigens can modulate HIV-1-specific immunity.

Highlights

CD8+ T cells play a major role in the immune response against HIV-1 infection
Cross-reactive microbial peptide candidates were selected by performing a pBLAST search and limiting results using guidelines from previously described biochemical studies [15,16]; we focused on the anchor residue and considered the P1, P3, and PO residues
The subject who did not respond to KK10 stimulation, a chronic progressor (CP) identified as CP4A, is infected with HIV-1 bearing the R264K escape mutation [17,18,19] which ablates binding of the KK10 epitope to the HLA-BÃ27 molecule

Summary

Introduction

CD8+ T cells play a major role in the immune response against HIV-1 infection. Potent HIV-specific CD8+ T cell responses are seen in the majority of subjects who naturally control viral replication (elite suppressors) [5,6,7,8,9,10]. Microbial peptides can modulate HIV-specific T cell responses presence of HIV-specific CD4+ T cell responses in HIV-negative subjects [11,12], but this phenomenon has not been as extensively explored in the context of the CD8+ T cell response to HIV-1. We hypothesized that microbial peptides that cross-react with HIV-1 peptides can modulate HIV-1-specific CD8+ T cell immunity. We chose to explore this hypothesis in the context of the HLA-BÃ27 allele, which has been associated with spontaneous control of HIV infection, as well as the HLA-AÃ02 allele, a common variant with broad clinical relevance. We focused on two epitopes in HIV-1 Gag, KK10 (Gag 263–272, KRWIILGLNK) and SL9 (Gag 77–85, SLYNTVATL), which are immunodominant in HLA-BÃ27+ [13] and HLA-A2+ [14] HIV-1 infected individuals, respectively

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