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

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.

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.

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^highTCF-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.

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.