This study explores HLA-E as a target to activate the immune system in HBV infection, identifying a stable peptide, Env371-379 L6I, that effectively triggers T-cell responses.
Hepatitis B virus
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Researchers have identified a potential new immunotherapeutic approach for chronic Hepatitis B (HBV) infection, often driven by T cell dysfunction. Chronic HBV infection is linked to elevated levels of the hepatitis B surface antigen (HBsAg), a protein that impairs T-cell responses. This study published in Nature focuses on a non-polymorphic molecule called HLA-E, which may offer a universal target for treating chronic infections like HBV.1
The research team characterized three variants of an HLA-E-binding peptide from the HBV envelope protein (Env371-379) using bioinformatics and laboratory assays. Among these, the Env371-379 L6I variant stood out as the most stable and capable of activating functional T cells. Using a T cell receptor (TCR)-anti-CD3 bispecific molecule, the researchers demonstrated that Env371-379 L6I could stimulate polyclonal T-cells when co-cultured with cells expressing HBsAg.1
The team also developed the a09b08 ImmTAV molecule, which specifically targets all three HLA-E-presented HBV Env371-379 peptide variants. "The a09b08 ImmTAV molecule specifically and potently targeted all three HLA-E-presented HBV Env371-379 peptide variants in T cell redirection assays with HBV Env-positive targets," the investigators said. "These characteristics were achieved by introducing multiple sequence modifications in the TCR CDR regions, generating novel interactions with both the peptide and HLA-E, as shown by structural analyses of the trimolecular peptide–HLA-E-TCR complexes." Additionally, CD8+ T cells specific to the HLA-E-Env371-379 L6I complex were detected in both HBV-naïve individuals and patients with chronic HBV after in vitro priming.1
A key limitation of this study is the absence of evaluation of the a09b08 ImmTAV molecule in HBV-infected primary human hepatocytes (PHH). Since HLA-E is expressed on most PHH and remains present on HBV-infected cells, it is possible that HLA-E expression could be further upregulated in an inflammatory liver environment, enhancing recognition by the ImmTAV molecule.1
In an exclusive email interview with Luis Da Silva Godinho, senior researcher at Immunocore, discussed the findings and their implications for future treatments of HBV, as well as the challenges that remain.
“We systematically searched for HLA-E binding peptides within the HBV proteome and the ILSP (from the envelope protein) was the only suitable candidate,” he explained. “When we looked at the most prevalent variants in that peptide region, we came across S3N and L6I variants. In physiological conditions the L6I is the only targetable peptide due to its higher stability, being able to compete with canonical peptides for HLA-E binding. It might be possible that there are other peptides variants that have the same characteristics of the L6I peptide variant but it will be strain/genotype dependent and not universally targetable.”
The study also found that other peptide variants might have similar characteristics to the L6I variant, but this would depend on the strain or genotype of HBV. “There might be other peptide variants that have the same characteristics of the L6I peptide variant, but it will be strain/genotype dependent and not universally targetable,” Godinho noted.
While the findings offer potential, Godinho highlighted the limitations of applying this approach to all HBV patients. The research would primarily apply to people with the L6I variant, which is more common in genotype E. “This approach would be limited to people with this variant which is more prevalent in genotype E. Safety is still a potential risk, more screening needs to be done to make sure there are no off-target reactivity. The biggest challenge is to determine if in human hepatocytes the level of target (pHLA-E L6I) is high enough for drug efficacy.” While the approach has promise, more research and testing are needed to ensure its effectiveness and safety in human trials.
Compared to existing HBV immunotherapies and vaccines, Godinho’s team believes their strategy could offer improvements. Current treatments for chronic HBV, such as nucleos(t)ide analogs and pegylated interferon alpha-2a, rarely lead to sustained loss of HBsAg or undetectable HBV DNA in the blood, which are necessary for a functional cure.
“Up to 15% of vaccinated individuals do not develop immunity against HBV and develop chronic HBV. Currently approved therapies for CHB (nucleos(t)ide analogs and pegylateted interferon alpha-2a) rarely lead to sustained loss of HBsAg and undetectable HBV DNA in serum, which are prerequisites for a functional cure. Our therapeutical approach using a TCR bispecific can achieve the elimination of viral reservoirs and sustain off-treatment responses after the therapy.”
The study explores HLA-E as a potential universal target for activating immune responses in chronic HBV by addressing T cell dysfunction.
Researchers identified the Env371-379 L6I variant as a highly stable peptide capable of activating T cells against HBV-infected cells.
The a09b08 ImmTAV molecule effectively redirects T cells to target HBV-infected cells by binding to HLA-E-presented peptides, enhancing immune responses.
This HLA-E-targeting strategy aligns with other recent efforts in HBV immunotherapy, such as another study we recently covered by Arbutus Biopharma's, which also aims to enhance immune responses in chronic HBV. Both strategies focus on overcoming T-cell dysfunction, a major challenge in treating chronic HBV infection.2
In the case of Arbutus’ therapy, described in the IM-PROVE I trial,, imdusiran (AB-729) uses RNA interference (RNAi) to reduce HBsAg levels, which alleviates the immune suppression caused by this protein. This reduction in HBsAg is crucial for restoring T-cell function and priming the immune system to better recognize and clear the virus. Additionally, imdusiran has been shown to activate the immune system, particularly T-cells, making treatments like interferon more effective.2
In contrast, the HLA-E-targeting strategy seeks to activate CD8+ T-cells directly through a novel immune redirection approach. By using engineered molecules like ImmTAV, this method directs T-cells toward HBV-infected cells via the HLA-E-Env371-379 peptide complex.1 Unlike imdusiran, which works by reducing surface antigen levels to alleviate immune suppression2, the HLA-E strategy focuses on stimulating the immune system to recognize and target HBV-infected cells more effectively.1
Overall, this study underscores the potential of HLA-E as a target for immune-based therapies and highlights the significant role of viral mutations in affecting the stability and effectiveness of immune responses. While both therapeutic approaches aim to enhance T-cell responses against chronic infection, they operate through distinct mechanisms: imdusiran works by reducing viral antigens to decrease immune tolerance, whereas the HLA-E strategy actively re-engages the immune system to target the virus. Together, these therapies represent complementary approaches in the evolving field of immune-based treatments for chronic HBV.
