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

Background Chronic hepatitis B virus (HBV) infection disproportionately affects people living with HIV, who are often excluded from functional cure studies. Objective 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 to inform 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, assessing transcriptomic and proteomic profiles, focusing on exhaustion markers alongside virus-specific functional capabilities. Results Transcriptomic analysis revealed distinct signatures in co-infection, with upregulation of TCR signalling genes, inhibitory pathways and progenitor-exhausted markers ( XCL2, TCF7, PDCD1, IL7R ). This profile scored highly for a precursor exhausted (Tpex) CD8 + T cell signature, reflecting stemness that maintains plasticity despite chronic antigen exposure. Proteomic analysis confirmed higher frequencies of Tpex (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. Tpex enrichment extended to HBV-specific populations corresponding with more robust, polyfunctional HBV-specific responses in co-infection against surface and core antigens. HBV-specific CD8 T cells maintained enhanced proliferative capacity and checkpoint responsiveness to anti-PDL1 blockade compared with HBV mono-infection. While co-infection was characterised by lower HBsAg levels and longer treatment duration, these factors alone did not account for the distinct immunological profiles. Conclusions People with well-controlled HBV/HIV co-infection maintain robust CD8 + T cell responses with preserved stem-like properties supporting antiviral function. These results challenge assumptions about additive immune dysfunction in dual chronic infections and highlight the need for tailored immune-modulatory therapies.