HIV/HBV co-infection remodels the immune landscape and Natural Killer cell functional responses

Background: Hepatitis B (HBV) and human immunodeficiency virus (HIV) co-infection is a common occurrence globally, with significant morbidity and mortality. Both viruses lead to dysregulated immune responses including changes in natural killer (NK) cells, a key component of antiviral defense and a promising target for HBV cure strategies. In this study we used high-throughput single cell analysis to explore the immune cell landscape in people with HBV mono-infection and HIV/HBV co-infection, on antiviral therapy, with emphasis on identifying the distinctive characteristics of NK cell subsets. Results: Our data show striking differences in the transcriptional programs of NK cells. HIV/HBV co-infection was characterized by an overrepresentation of adaptive, KLRC2 expressing NK cells, including a higher abundance of a chemokine enriched (CCL3/CCL4) adaptive cluster. The NK cell remodeling in HIV/HBV co-infection was reflected in enriched activation pathways shared with T cells, including CD3 phosphorylation and ZAP-70 translocation that can mediate stronger ADCC responses and a bias towards chemokine/cytokine signaling. By contrast HBV mono-infection imposed a stronger cytotoxic profile on NK cells and a more prominent signature of exhaustion with higher circulating levels of HBsAg. Mirroring the transcriptomic analysis, phenotypic alterations in the NK cell pool in co-infection were consistent with increased ‘adaptiveness’ and better capacity for ADCC compared to HBV mono-infection. Overall an adaptive NK cell signature correlated inversely with circulating levels of HBsAg and HBV-RNA in our cohort. Conlcusions: This study provides new insights into the differential transcriptional signature and functional profile of NK cells in HBV and HIV/HBV co-infection, highlighting new pathways that can be manipulated to tailor NK cell-focused approaches to advance cure strategies in the different population groups.