Preserved CD4 ⁺ T cell helper function and coordinated antiviral immunity in people with HBV/HIV co-infection on long-term therapy

Background & Aims

People with HBV/HIV co-infection on antiretroviral therapy achieve higher rates of HBV functional cure than those with HBV mono-infection, yet the immunological basis remains poorly characterised. HBV-specific CD4 ⁺ T cell responses are critical for viral control and functional cure but have been scarcely examined in HBV/HIV co-infection. Our previous studies in HBV/HIV co-infection demonstrated preserved stem-like CD8 ⁺ T cells and NK cell functional responses, but whether CD4 ⁺ T cell helper function is similarly maintained is unknown.

Methods

We analysed CD4 ⁺ T cell responses in 72 participants (HBV n=26, HBV/HIV n=24, HIV n=22) on suppressive antiviral therapy, using multiparameter flow cytometry, virus-specific CD4 ⁺ T cell functional assays and proliferation assays.

Results

People with HBV/HIV co-infection had significantly higher HBV envelope- and core-specific CD4 ⁺ T cell responses, with IL-2 production particularly discriminating between groups. CD4 ⁺ T cell responses to CEF (CMV, EBV, and Influenza) were comparable, confirming antigen specificity. Granzyme B-expressing cytotoxic CD4 ⁺ T cells and TCF-1 ⁺ CD127 ⁺ PD-1 ⁺ CD4 ⁺ T cells were enriched in co-infection. CD4 ⁺ and CD8 ⁺ T cell responses were more frequently coordinated within donors in co-infection than in mono-infection (envelope 83% vs 50%; core 94% vs 60%), where they were more often uncoupled. IL-2 producing CD4 ⁺ T cells correlated with CD8 ⁺ T cell responses and the CD4:CD8 ratio in co-infection. HBV-specific proliferative capacity was enhanced in co-infection.

Conclusions

People with HBV/HIV co-infection mount functional HBV-specific CD4 ⁺ T helper responses that are coordinated with CD8 ⁺ T cell immunity at the individual level. Together with our prior findings of preserved NK and CD8 ⁺ T cell responses in this cohort, these data identify treated HBV/HIV co-infection as a setting of integrated, rather than compromised, antiviral immunity.

Impact and Implications

People with HBV/HIV co-infection can achieve HBV functional cure more frequently than people with HBV mono-infection, but the immune mechanisms remain unclear. This study shows that treated HBV/HIV co-infection is characterised by functional HBV-specific CD4⁺ helper responses and coordinated CD4⁺/CD8⁺ antiviral immunity. These responses were most strongly associated with the CD4:CD8 ratio, a routinely available clinical marker, rather than with CD4 count alone. These findings argue that people with HBV/HIV co-infection should be prioritised in, not excluded from, HBV cure immunotherapy trials.

Graphical Abstract