Gene Discovery in CHB Patients to Identify Unknown Pathways That Lead to B and NK Cell Deregulation (LiNKeB2)

Natural Killer (NK) and B cell immune responses occur during the early stages of infection and are essential to eradicate it. Yet, chronic hepatitis B (CHB) infection occurs because the antiviral immune response is insufficient. In both NK and B cell studies we will explore the genetic alterations that occur during the varied chronic stages of the disease. We believe that our findings will allow us to understand the molecular signature of NK and B cells in the context of HBV infection.

Study Overview

• Status: Recruiting
• Conditions: Chronic Hepatitis B Virus
• Intervention / Treatment: Other: blood sample HBV patient; Other: blood sample healthy volunteers

Detailed Description

Thanks to past ANRS funding we showed that both B and NK cells are dysfunctional in Hepatitis B virus (HBV) in in vitro human models and validated in patients with chronic infection. We observed that B cells responses by Toll Like Receptor 9 (TLR9) were inhibited by the HBV viral protein HBsAg. We noted the loss of TLR9 expression on all B cell subsets by HBV was mediated by loss of its promoter activity by blocking the phosphorylation of the transcription factor CREB (pCREB). Furthermore, B cell-TLR9 mediated responses such as proliferation and cytokine production were abrogated in CHB patients. For NK cells we demonstrated several significant changes in their receptor expression, loss of cytokines IFN γ, MIP1a and cytotoxicity compared to healthy donors. However, for both NK and B cell dysfunction the molecular basis and signaling pathway of this phenomenon are poorly characterized and whether this state can be reversed, a question of therapeutic importance, is unknown. We hypothesize that several molecular changes occur in NK cells from CHB patients that depend on altering the mTOR pathway by HBV and more specifically by HBsAg. Together our results from this proposal should define the genetic signatures that lead to B and NK cell function and will contribute to our understanding on immune dysfunction by HBV. In both NK and B cell studies we will explore the genetic alterations that occur during the varied chronic stages of the disease. This can only be investigated in patients including all clinical stages of CHB.

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Paul CARRIER, MD; Phone Number: +335 55 05 80 22; Email: paul.carrier@chu-limoges.fr

Study Locations

• France
  • Limoges, France, 87042
    • Recruiting
    • Limoges University Hospital
    • Principal Investigator: Véronqiue LOUSTAUD-RATTI, MD
  • Limoges, France, 87042
    • Recruiting
    • Centre d'investigation Clinique
    • Principal Investigator: Fabienne MARIAUD, MD
  • Lyon, France, 69004
    • Recruiting
    • Hospice civils de Lyon
    • Principal Investigator: Fabien ZOULIM, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Male or female, age ≥18 years old
• HBV infection or chronic HBV infection untreated or treated with a nucleoside or nucleotide analog
• Willing and able to provide written informed consent
• Affiliated with a social securityregimen

Healthy volunteer must meet all of the following inclusion criteria to be eligible for participation in this study:

• Male or female, age between 18 and 80 years
• Willing and able to provide written informed consent

Exclusion Criteria:

• Co-infection with HCV, HIV or HDV (or HBV for healthy volunteer)
• Acute hepatitis in the year preceding recruitment
• Other liver diseases : alcohol, obesity (BMI>30), diabetes, metabolic syndrome (dyslipidemia and/or known hypertension) - Underlying immunological or cancerous diseases
• Patient with a disability that prevents him/her from fully understanding the requirements of the trial - Patient under court protection, guardianship or curatorship
• Pregnant or breast-feeding women.

Secondary exclusion criteria:

• A healthy volunteer whose vaccination status does not match that expected on the basis of serological results
• Positive blood pregnancy test on inclusion
• Positive HCV, HIV or HDV test in a patient
• Positive HBV, HCV, HIV or HDV test in a healthy volunteer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: HBV patient; a blood sample is done during a follow-up visit	Other: blood sample HBV patient; During a boold sample at only one follow up visit: 3 tubes EDTA 10 ml per patient; 1 tube "Paxgene" 1ml; 2 dry tube per patient
Other: healthy volunteers; a blood sample	Other: blood sample healthy volunteers; 3 tubes EDTA ideally age and sex matched to CHB patient.; 1 tube "Paxgene" 1ml; 2 dry tube

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
RNA sequencing of B cells from CHB patients at different stages, description of their molecular signature	At inclusion, day 0

Secondary Outcome Measures

Outcome Measure	Time Frame
RNA sequencing of NK cells from CHB patients at different stages, description of their molecular signature (protein expression measured by flow cytometry)	At inclusion, day 0

Collaborators and Investigators

• Sponsor: University Hospital, Limoges
• Collaborators: National Agency for Research on AIDS and Viral Hepatitis (ANRS)
• Investigators: Principal Investigator: Paul CARRIER, MD, University Hospital, Limoges

Study record dates

Study Major Dates

• Study Start (Actual): August 12, 2025
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): October 1, 2028

Study Registration Dates

• First Submitted: February 25, 2025
• First Submitted That Met QC Criteria: February 25, 2025
• First Posted (Actual): March 3, 2025

Study Record Updates

• Last Update Posted (Actual): May 20, 2026
• Last Update Submitted That Met QC Criteria: May 19, 2026
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: HBV; B cells; TLR9; NK celles
• Additional Relevant MeSH Terms: Blood-Borne Infections; Pathologic Processes; Chronic Disease; Disease Attributes; Infections; Virus Diseases; Digestive System Diseases; Liver Diseases; Hepatitis, Viral, Human; Communicable Diseases; DNA Virus Infections; Hepadnaviridae Infections; Hepatitis, Chronic; Hepatitis; Pathological Conditions, Signs and Symptoms; Hepatitis B; Hepatitis B, Chronic
• Other Study ID Numbers: 87RI24_0023 (LiNKeB2)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No