Viral sequence determines HLA-E-restricted T cell recognition of hepatitis B surface antigen

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• Chronic Hepatitis B virus (HBV) infection leads to T cell dysfunction.
• Hepatitis B surface antigen (HBsAg) contributes to T cell impairment.
• The non-polymorphic HLA-E molecule presents a potential target for immunotherapies.

Purpose of the Study:

• To characterize genotypic variants of an HLA-E-binding HBsAg peptide (Env371-379).
• To assess the functional response of T cells to different HBsAg peptide variants presented by HLA-E.
• To explore the potential of HLA-E-restricted HBsAg peptides as targets for immunotherapy.

Main Methods:

• Bioinformatic prediction of HBsAg peptide variants.
• Biochemical and cellular assays to verify peptide variants.
• Use of a soluble affinity-enhanced T cell receptor (TCR)-anti-CD3 bispecific molecule to probe HLA-E presentation.
• Co-culture assays with T cells and target cells expressing HBsAg.

Main Results:

• Three genotypic variants of the Env371-379 peptide were identified and verified.
• Only the L6I variant of Env371-379 elicited functional T cell responses when presented by HLA-E.
• HLA-E-Env371-379 L6I-specific CD8+ T cells were detected in both HBV-naïve and chronically infected individuals after in vitro priming.
• Viral mutations impact the stability and targetability of peptide-HLA-E complexes.

Conclusions:

• Evidence for HLA-E-mediated presentation of HBV Env peptides is provided.
• The stability of the peptide-HLA-E complex is crucial for eliciting T cell responses.
• Specific HBsAg peptide variants, like L6I, are potential targets for developing universal immunotherapies against chronic HBV.