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

ObjectiveChronic 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. DesignWe 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. ResultsTranscriptomic 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 ToxhighTCF-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. ConclusionOur 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 TOPICO_LIChronic 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. C_LI WHAT THIS STUDY ADDSO_LIOur 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. C_LIO_LIPeople 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. C_LIO_LIOur data demonstrate intrinsic differences in T cell profiles, revealing a paradoxical increase in terminally exhausted CD8 T cells in people with HBV mono-infection. C_LI HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYO_LIBy 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. C_LIO_LIFurthermore, 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. C_LI