Persistent hepatitis B virus and HIV coinfections in dually humanized mice engrafted with human liver and immune system

Abstract

Chronic hepatitis B (CHB), caused by hepatitis B virus (HBV), remains a major medical problem. HBV has a high propensity for progressing to chronicity and can result in severe liver disease, including fibrosis, cirrhosis, and hepatocellular carcinoma. CHB patients frequently present with viral coinfection, including human immunodeficiency virus type (HIV) and hepatitis delta virus. About 10% of chronic HIV carriers are also persistently infected with HBV, which can result in more exacerbated liver disease. Mechanistic studies of HBV-induced immune responses and pathogenesis, which could be significantly influenced by HIV infection, have been hampered by the scarcity of immunocompetent animal models. Here, we demonstrate that humanized mice dually engrafted with components of a human immune system and a human liver supported HBV infection, which was partially controlled by human immune cells, as evidenced by lower levels of serum viremia and HBV replication intermediates in the liver. HBV infection resulted in priming and expansion of human HLA-restricted CD8+ T cells, which acquired an activated phenotype. Notably, our dually humanized mice support persistent coinfections with HBV and HIV, which opens opportunities for analyzing immune dysregulation during HBV and HIV coinfection, and preclinical testing of novel immunotherapeutics.

Mathematical Models of Early Hepatitis B Virus Dynamics in Humanized Mice

“…Humanized mice were generated by engrafting human hepatocytes (HEP mice) or hepatocytes and human immune cells (HEP/HIS mice) into immunodeficient xenorecipient strains (for details please see Hogan et al. ( 2023 )). Human hepatic and/or hematopoietic engraftment was quantified prior to infection with HBV.…”

“…Mice are either singly engrafted with human hepatocytes (HEP) Hogan et al. ( 2023 ); Gutti et al. ( 2014 ); Dusséaux et al.…”

“…( 2017 ) or dually co-engrafted with human hepatocytes and components of a human immune system (HEP/HIS) Hogan et al. ( 2023 ); Billerbeck et al. ( 2016 ); Dusséaux et al.…”

“…In this study, we analyzed data from two groups of either HEP or HEP/HIS mice challenged with HBV for which longitudinal sHBV and longitudinal HBsAg titers were collected biweekly for up to six weeks following infection Hogan et al. ( 2023 ). HBsAg is believed to serve as both decoy against humoral immune responses Ciupe et al.…”

“…Mice in the HEP/HIS group had lower sHBV and HBsAg levels than HEP mice, suggesting that the grafted human immune system mounts an antiviral response, which can, at least partially, control HBV infection Hogan et al. ( 2023 ). Several mechanisms may explain the observed differences: either (partial) loss/death of productively HBV-infected cells i.e.…”