Virus-specific T cells and neutralizing antibodies are independent correlates of long-term protective immunity against hepatitis C virus
7 affiliations
- 1Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, Quebec, Canada
- 2Département de microbiologie et immunologie, Université de Montréal, Montréal, Quebec, Canada
- 3Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Giza, Egypt
- 4School of Pharmacy, Newgiza University, Giza, Egypt
- 5Department of Medical Microbiology and Immunology, Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, Alberta, Canada
- 6Département de médecine familiale, Université de Montréal, Montréal, Quebec, Canada
- 7Département de médecine, Université de Montréal, Montréal, Quebec, Canada
Abstract
Virus-specific T cells and broadly neutralizing antibodies (NAbs) are associated with spontaneous clearance of acute primary hepatitis C virus (HCV) infection and reinfection. Following spontaneous clearance, HCV-specific memory T cells are long-lived, but NAbs are less durable. How these two arms contribute to long-term protective immunity upon re-exposure is unknown. Herein, we compared the magnitude and breadth of memory HCV-specific T cells and NAbs in a cohort of HCV-spontaneously resolved people who inject drugs with high-risk exposure to the virus but who remained free of observed reinfections (FOR, n = 34) or who got reinfected (n = 22). Among FOR, 73.5% (n = 25) exhibited high frequencies of gamma interferon (IFN-γ)-producing T cells, while 23.5% (n = 8) showed high neutralization breadth (>25% neutralization of HCV pseudoparticles [HCVpp]) and/or potency (geometric mean neutralization >50% against seven HCVpp). Notably, some subjects had detectable NAbs several years after clearance. Multivariate random forest analysis demonstrated that the frequency of IFN-γ-producing T cells and the NAb response against only one difficult-to-neutralize HCVpp (1b58) were significant predictors of protection against reinfection (P < 0.05). Longitudinal analysis of the immune response in subjects with multiple episodes of infection showed that strong and broad HCV-specific T cell responses were associated with spontaneously cleared episodes. In contrast, NAbs did not protect from chronicity upon re-exposure in the absence of memory T cells, or if they were unable to recognize the infecting virus due to imprinting by strains of the previous episodes. In conclusion, T cell responses and NAbs targeting specific isolates are independent predictors of long-term protective immunity against HCV.
IMPORTANCE: Hepatitis C virus (HCV) is a blood-borne virus that disproportionately affects people who inject drugs. Most HCV infections become persistent, leading to liver fibrosis and cancer. Although effective antiviral therapies are available, around 50 million people remain persistently infected with HCV and can transmit the virus. Currently, there is no available vaccine to control the spread of HCV. However, around one in four people infected can naturally clear the virus, becoming partially protected upon re-exposure, suggesting it is possible to develop a vaccine that induces similar protection. In this study, we investigated the contribution of T cells and neutralizing antibodies to protection against observed reinfection in a cohort of people who inject drugs and have naturally cleared HCV, yet remain at high-risk exposure. Our findings suggest that strong T cell responses and neutralizing antibodies targeting hard-to-neutralize isolates could predict protective immunity upon reinfection.
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BibTeX
@article{gomezescobar2026virusspecific,
title = {{Virus-specific T cells and neutralizing antibodies are independent correlates of long-term protective immunity against hepatitis C virus}},
author = {Elsa Gomez-Escobar and Asiyah Siddique and Omar Khedr and Nathalie Bédard and Alizée Fieffé-Bédard and Nourtan F. Abdeltawab and Nicol Flores and Mohamed S. Abdel-Hakeem and Mohamed Eisa and Geng Zang and John Lok Man Law and Juthika Kundu and Michael Houghton and Julie Bruneau and Naglaa H. Shoukry},
journal = {Journal of Virology},
year = {2026},
month = sep,
doi = {10.1128/jvi.00849-26},
url = {https://doi.org/10.1128/jvi.00849-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Virus-specific T cells and neutralizing antibodies are independent correlates of long-term protective immunity against hepatitis C virus
AU - Elsa Gomez-Escobar
AU - Asiyah Siddique
AU - Omar Khedr
AU - Nathalie Bédard
AU - Alizée Fieffé-Bédard
AU - Nourtan F. Abdeltawab
AU - Nicol Flores
AU - Mohamed S. Abdel-Hakeem
AU - Mohamed Eisa
AU - Geng Zang
AU - John Lok Man Law
AU - Juthika Kundu
AU - Michael Houghton
AU - Julie Bruneau
AU - Naglaa H. Shoukry
PY - 2026
DA - 2026/09/10
JO - Journal of Virology
DO - 10.1128/jvi.00849-26
UR - https://doi.org/10.1128/jvi.00849-26
AB - Virus-specific T cells and broadly neutralizing antibodies (NAbs) are associated with spontaneous clearance of acute primary hepatitis C virus (HCV) infection and reinfection. Following spontaneous clearance, HCV-specific memory T cells are long-lived, but NAbs are less durable. How these two arms contribute to long-term protective immunity upon re-exposure is unknown. Herein, we compared the magnitude and breadth of memory HCV-specific T cells and NAbs in a cohort of HCV-spontaneously resolved people who inject drugs with high-risk exposure to the virus but who remained free of observed reinfections (FOR, n = 34) or who got reinfected (n = 22). Among FOR, 73.5% (n = 25) exhibited high frequencies of gamma interferon (IFN-γ)-producing T cells, while 23.5% (n = 8) showed high neutralization breadth (>25% neutralization of HCV pseudoparticles [HCVpp]) and/or potency (geometric mean neutralization >50% against seven HCVpp). Notably, some subjects had detectable NAbs several years after clearance. Multivariate random forest analysis demonstrated that the frequency of IFN-γ-producing T cells and the NAb response against only one difficult-to-neutralize HCVpp (1b58) were significant predictors of protection against reinfection (P < 0.05). Longitudinal analysis of the immune response in subjects with multiple episodes of infection showed that strong and broad HCV-specific T cell responses were associated with spontaneously cleared episodes. In contrast, NAbs did not protect from chronicity upon re-exposure in the absence of memory T cells, or if they were unable to recognize the infecting virus due to imprinting by strains of the previous episodes. In conclusion, T cell responses and NAbs targeting specific isolates are independent predictors of long-term protective immunity against HCV. IMPORTANCE: Hepatitis C virus (HCV) is a blood-borne virus that disproportionately affects people who inject drugs. Most HCV infections become persistent, leading to liver fibrosis and cancer. Although effective antiviral therapies are available, around 50 million people remain persistently infected with HCV and can transmit the virus. Currently, there is no available vaccine to control the spread of HCV. However, around one in four people infected can naturally clear the virus, becoming partially protected upon re-exposure, suggesting it is possible to develop a vaccine that induces similar protection. In this study, we investigated the contribution of T cells and neutralizing antibodies to protection against observed reinfection in a cohort of people who inject drugs and have naturally cleared HCV, yet remain at high-risk exposure. Our findings suggest that strong T cell responses and neutralizing antibodies targeting hard-to-neutralize isolates could predict protective immunity upon reinfection.
SN - 0022-538X
SN - 1098-5514
ER -