Stem-like CD8+ T cells preserve HBV-specific responses in HBV/HIV co-infection

Abstract Objective Chronic HBV infection disproportionately affects people living with HIV, who are often excluded from functional cure studies. This study investigates CD8 + T cell profiles in HBV mono-infection versus HBV/HIV co-infection, examining the impact of long-term therapy on virus-specific responses with the goal of informing therapeutic strategies for immune restoration. Design We analysed CD8 + T cell responses in 61 participants (HBV n=20, HBV/HIV n=20, HIV n=21), on suppressive antiviral therapy. We assessed transcriptomic and proteomic profiles, focusing on exhaustion markers alongside virus-specific functional capabilities. Results Transcriptomic analysis revealed a distinct signature in co-infection, with upregulation of genes associated with TCR signaling, inhibitory pathways and progenitor-exhausted markers ( XCL2, TCF7, PDCD1, IL7R ). This gene profile scored highly for a precursor exhausted (Tpex) CD8+ T cell signature, reflecting a "stemness" programme that maintains plasticity despite chronic antigen exposure. Proteomic analysis confirmed higher frequencies of precursor exhausted TCF-1 + CD127 + PD-1 + CD8 + T cells in co-infection, while HBV mono-infection showed predominance of terminally exhausted Tox high TCF-1 - CD127 - cells. These differences correlated with more robust, polyfunctional HBV-specific responses in co-infection against surface and core antigens. Lower HBsAg levels and longer treatment duration in co-infection associated positively with Tpex populations and functional responses and inversely with terminal exhaustion. Conclusion Our findings demonstrate that individuals with well-controlled HBV/HIV co-infection maintain more robust CD8 + T cell responses with preserved stem-like properties supporting ongoing antiviral function. These results underscore the benefits of early antiretroviral intervention and the need for tailored immune-modulatory therapies to restore antiviral functionality in these diverse patient populations. WHAT IS ALREADY KNOWN ON THIS TOPIC Chronic hepatitis B virus (HBV) infection is marked by a progressive dysfunction of CD8⁺ T cells, which are crucial for antiviral responses. Traditionally these responses were thought to be more severely impacted in people with HBV/HIV co-infection. WHAT THIS STUDY ADDS Our study provides new insights into the heterogeneous functional profiles of HBV-specific CD8⁺ T cells in people with HBV and HBV/HIV co-infection in the current antiretroviral therapy (ART) era. People living with HBV/HIV co-infection suppressed on antivirals have a higher prevalence of precursor exhausted CD8⁺ T cells (Tpex), alongside more effective antiviral responses when compared to those with HBV mono-infection. Our data demonstrate intrinsic differences in T cell profiles, revealing a paradoxical increase in terminally exhausted CD8⁺ T cells in people with HBV mono-infection. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY By providing a clearer understanding of CD8⁺ T cell dynamics in HBV mono-infection and HBV/HIV co-infection, our findings could inform the design of tailored immunotherapies aimed at revitalising antiviral responses. Furthermore, this research may influence practices regarding clinical management emphasising the need for early intervention strategies and individualised approaches tailored to T cell profiles rather than solely based on infection status.