Immune Remodeling in People Living with HIV/HBV Co-Infection on Long-Term Therapy: Revisiting the Paradigm of Additive Dysfunction [Letter]

We read with interest the review by Bobadilla et al, which provides a valuable synthesis of hepatic viral reservoirs in people living with both HIV and HBV. 1 The authors make a compelling case for the liver as a multicellular reservoir for both viruses and rightly advocate for integrated cure strategies and the inclusion of people with co-infection in clinical trials.Their description of nuclear persistence mechanisms, stellate cell and Kupffer cell biology, and the gut-liver axis contribution to disease progression is a useful framework for the field.We share their position to include people living with HIV/HBV co-infection in HBV cure trials, a population that remains disproportionately excluded despite bearing the greatest disease burden.The review frames immune dysfunction in co-infection as "synergistic reinforcement", a model in which the two viruses together produce a uniformly worse immunological state than either alone, that requires further qualification.While this may reflect the landscape of untreated or partially treated disease, emerging data from treated cohorts, including our own, do not fully support this assumption and point to a more complex picture.We believe this distinction is important, as it directly influences whether people with co-infection are considered appropriate candidates for immune-based cure strategies.In two recent studies using single cell RNA sequencing and functional assays in well characterised cohorts on longterm suppressive therapy, we have found that people with HBV/HIV co-infection display more favourable immunological profiles and lower levels of peripheral surrogate markers of HBV viral activity compared to those with HBV monoinfection.In our study published in Hepatology, people with co-infection showed an overrepresentation of adaptive NK cells with enhanced ADCC capacity, alongside lower circulating HBsAg and HBV-RNA levels; an adaptive NK cell signature correlated inversely with these virological parameters across the cohort.2 In our subsequent study in Gut, we found that people with co-infection maintained more robust HBV-specific CD8+ T cell responses than those with HBV alone, with enrichment of stem-like precursor exhausted (Tpex) populations that retained proliferative capacity and responsiveness to PD-L1 checkpoint blockade.3 HBsAg levels were significantly lower in co-infection, with a greater proportion of individuals achieving levels below 50 IU/mL.Across both studies, people with co-infection did not exhibit the degree of immune dysfunction that a model of synergistic reinforcement would predict; rather, they showed evidence of immune remodelling that may favour viral control.These observations may offer a mechanistic basis for the higher rates of HBsAg clearance reported in people with co-infection following initiation of HBV-active ART, a phenomenon the review identifies but describes as "poorly understood."The preservation of Tpex CD8+ T cells that mediate the proliferative burst following checkpoint blockade, combined with enhanced adaptive NK cell ADCC, may collectively contribute to the immune reconstitution that facilitates functional cure.Along these lines, people with well controlled co-infection may be particularly suitable candidates for immune-based cure approaches rather than a population assumed to have limited capacity for immune-mediated viral control.