Spatial omics to understanding HBV control in people with HIV coinfection

About This Grant

PROJECT SUMMARY/ABSTRACT Hepatitis B (HBV) infects more than 200 million people worldwide and is the 10th leading cause of death worldwide. HBV treatment with nucleoside analogs targets the suppression of viral replication, but HBV able to persist in a reservoir of covalently closed circular (cccDNA) form during chronic infection, with the potential to reactivate upon immune suppression, aging, or cessation of treatment. As a consequence, lifelong treatment is required, and eradication and functional cure of the infection, the loss of surface antigen in serum testing, occurs at a slow rate. Moreover, HBV suppression with current therapies does not eliminate the risk of liver cancer development. HIV coinfection with HBV is common and complicates HBV outcomes, evidenced by an 18-fold increased liver-related mortality, compared to HBV alone. Novel approaches to HBV therapy are needed, particularly in people with HBV/HIV. While HIV accelerates the HBV clinical course, it also presents unique scientific opportunities as shortly after starting HBV-active antiretroviral therapy (ART), some people with HBV/HIV experience higher rates of HBsAg loss, 5 times what is seen in HBV alone. Leveraging an established clinical cohort with HBV/HIV and HBV in Zambia, we will analyze the impact of HIV-related immune suppression and restoration with ART on HBV liver reservoir and the liver microenvironment using cutting-edge spatial proteomic and transcriptomic technologies. These technologies, which are capable of delineating RNA, DNA, and protein targets without cellular or tissue dissociation at subcellular resolution, will be applied to liver biopsies from cohort participants before and during therapy, allowing us to investigate and determine cellular composition, HBV- and HIV-infected cells, spatial architecture, and the hepatic microenvironment. The resulting data will advance the development of HBV cure, particularly for people with HIV, by identifying how HIV accelerates liver pathogenesis, whether these mechanisms are normalized with ART, and virus-host interactions in the liver that mediate HBV control including FC. This line of research will validate current mechanisms being evaluated in trials and pave the way for new and emerging immunotherapies for HBV cure.