Hepatitis B virus-specific CD4 T cell responses differentiate functional cure from chronic surface antigen+ infection

Hoogeveen, Ruben C.; Dijkstra, Suzan; Bartsch, Lea M.; Drescher, Hannah K.; Aneja, Jasneet; Robidoux, Maxwell; Cheney, James A.; Timm, Jörg; Gehring, Adam J.; Sousa, Paulo Sérgio Fonseca de; Ximenez, L. Lewis; Peliganga, Luis Baião; Pitts, Anita; Blackburn, Fiona Evans; Boonstra, André; Kim, Arthur Y.; Lewis-Ximenez, Lia Laura; Lauer, Georg M.

doi:10.1016/j.jhep.2022.05.041

Cited by 19 publications

(11 citation statements)

References 31 publications

(34 reference statements)

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“…For three decades, we have known that HBV-specific T cell immunity differs between patients with acute and CHB (reviewed in Chisari and Ferrari 2). More recent works have shown that HBV-specific T cells recover, even though often only partially,3 4 after functional cure 5 6. Such data support the idea that restoration of functional HBV-specific T cell immunity can achieve HBV control but fails to take into account a key characteristic of HBV-specific T cells in CHB patients: their extreme heterogeneity 3 7–9…”

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confidence: 59%

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Quest for immunological biomarkers in the management of CHB patients

Bertoletti

Bert

2023

Gut

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confidence: 59%

“…Rossi’s EI score, that predicts restoration of CD8T cell function alone has inherent limitations, since CD4T cells are an essential part of immune reconstitution after functional cure 6. There is also a growing awareness that analysis of frequency and levels of Th1 cytokine secretion are insufficient to define the heterogeneity of HBV-specific T cells.…”

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confidence: 99%

Quest for immunological biomarkers in the management of CHB patients

Bertoletti

Bert

2023

Gut

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“…They also suggest the need to better understand HBV immunity in people with HBV/HIV coinfection. In people with HBV monoinfection, the quantity and functionality of HBV-specific CD4 þ T cells was associated with HBV functional cure [15]. Similar data among PWH are lacking.…”

Section: Discussionmentioning

confidence: 96%

HBV viral replication markers and hepatic fibrosis in untreated chronic HBV infection with and without HIV coinfection in Zambia

Muula

Bosomprah

Sinkala

et al. 2023

Aids

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Background: To inform novel therapies, a more nuanced understanding of HIV's impact on hepatitis B virus (HBV) natural history is needed, particularly in high burden countries. Methods: In Lusaka, Zambia, we compared prospectively-recruited adults (18+ years) with chronic HBV infection, with and without HIV, pre-therapy. We excluded those with treatment-experience or HBV diagnosis due to clinical suspicion. We assessed HBV DNA levels, hepatitis B e antigen, CD4 (if coinfection), and liver disease (transient elastography [TE], serum alanine aminotransferase). In multivariable analyses, we evaluated the association of HIV overall and by level of CD4 count on these markers. Results: Among 713 adults analyzed, median age was 33 years, 63.0% were male, and 433 had HBV/HIV coinfection. Median CD4 count was 200 cells/mm3. HBV DNA was >2,000 IU/ml for 311 (51.0%) and 227 (32.5%) were HBeAg-positive. 15.5% had advanced fibrosis or cirrhosis. HIV coinfection was associated with 5-fold increased HBV DNA levels (adjusted geometric mean ratio, 5.78; 95% confidence interval, 2.29–14.62) and 2 times the odds of HBeAg-positivity (adjusted odds ratio, 2.54; 95% CI, 1.59–4.08). These associations were significant only at CD4 counts 100–350 and <100 cells/mm3. HIV was not associated with markers of fibrosis or ALT. Discussion: HIV's impact on HBV natural history likely depends on the degree and duration of immune suppression. There is strong rationale to monitor HBV DNA in people with HBV/HIV coinfection and immune suppression. A better understanding is needed of mechanisms of increased liver-related mortality in people with HBV/HIV coinfection.

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“…Immune intervention using interferon-a is effective only in a small subset of HBV carriers and is not particularly effective in CHB patients with genotype C, which is endemic in Asian nations, including China, Japan and South Korea (36). For a functional cure of chronic HBV infections, induction of HBV-specific T-cell activation is necessary, which can be achieved through the use of immunotherapeutic agents capable of breaking the systemic immune tolerance in chronic carriers (37,38). Dendritic cells (DCs), major antigen-presenting cells, can cross-present extracellular antigens to CD8+ T cells and induce cytotoxic T lymphocyte (CTL) responses (39).…”

Section: Discussionmentioning

confidence: 99%

A hepatitis B virus-derived peptide combined with HBsAg exerts an anti-HBV effect in an HBV transgenic mouse model as a therapeutic vaccine

et al. 2023

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IntroductionFor complete or functional cure of hepatitis B virus (HBV) infection, application of immunotherapy is now being attempted. Recently, we reported that a 6-mer hepatitis B virus (HBV)-derived peptide, Poly6, exerts a strong anticancer effect in tumor-implanted mice through inducible nitric oxide synthase (iNOS)-producing DCs (Tip-DCs) in a type 1 interferon (IFN-I)-dependent manner, suggesting its potential as a vaccine adjuvant.MethodsIn this study, we explored the potential of Poly6 in combination with HBsAg as a therapeutic vaccine against hepatitis B virus infection. We investigated the immunotherapeutic potential of Poly6 combined with HBsAg vaccination against hepatitis B virus infection in C57BL/6 mice or an HBV transgenic mouse model.ResultsIn C57BL/6 mice, Poly6 enhanced DC maturation and DC migration capacity in an IFN-I-dependent manner. Moreover, the addition of Poly6 to alum in combination with HBsAg also led to enhanced HBsAg-specific cell-mediated immune (CMI) responses, suggesting its potential as an adjuvant of HBsAg-based vaccines. In HBV transgenic mice, vaccination with Poly6 combined with HBsAg exerted a strong anti-HBV effect via induction of HBV-specific humoral and cell-mediated immune responses. In addition, it also induced HBV-specific effector memory T cells (TEM).DiscussionOur data indicated that vaccination with Poly6 in combination with HBsAg exerts an anti-HBV effect in HBV transgenic mice, which is mainly mediated by HBV-specific CMI and humoral immune responses via IFN-I-dependent DC activation, suggesting the feasibility of Poly6 as an adjuvant for an HBV therapeutic vaccine.

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Hepatitis B virus-specific CD4 T cell responses differentiate functional cure from chronic surface antigen+ infection

Cited by 19 publications

References 31 publications

Quest for immunological biomarkers in the management of CHB patients

Quest for immunological biomarkers in the management of CHB patients

HBV viral replication markers and hepatic fibrosis in untreated chronic HBV infection with and without HIV coinfection in Zambia

A hepatitis B virus-derived peptide combined with HBsAg exerts an anti-HBV effect in an HBV transgenic mouse model as a therapeutic vaccine

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