UCSF researchers have generated and validated mouse models of hepatitis B virus (HBV) infection that recapitulate the key differences in viral clearance and persistence between early life (resulting primarily in chronic infections) and adulthood infection (often acute infections). The two transgenic mouse models – HBVRplRag and HBVEnvRag – offer a novel system for studying primary HBV infection for use in drug discovery and vaccine research.
HBV infection can lead to chronic infections that result in 0.6 million deaths per year worldwide by causing liver failure and cancer. Clearance of HBV infection is age dependent, with the majority of adult-acquired infections leading to spontaneous clearance, whereas infection in young children often leads to chronic infections. To study these early events of infection and immune activation that lead to HBV clearance or persistence, in vivo models are needed to screen and validate lead drug candidates. HBV cannot infect mice, however, researchers at UCSF have generated transgenic mouse models that mimic critical features of primary HBV infection observed in humans.
The UCSF investigators have generated two HBV-transgenic mouse systems that can be used to reveal disease mechanisms involved in human HBV immunopathogenesis: HBVEnvRag - Rag1-deficient mouse expressing viral antigens (HBV small, middle and large envelope proteins) in the liver, and HBVRplRag - Rag1-deficient mouse that allows viral replication and release of infectious virions.
Reconstitution of these novel transgenic mice with naïve B and T cells results in immune responses that occur in a natural primary HBV infection. Detailed information on the HBV mouse models can be found in the recent publication:
Publicover J, Goodsell A, Nishimura S, Vilarinho S, Wang ZE, Avanesyan L, Spolski R, Leonard WJ, Cooper S, Baron JL. IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B. The Journal of Clinical Investigation. 2011 Mar 1;121(3):1154-62.
This breakthrough work in HBV research was also highlighted in the following articles:
The investigators welcome the opportunity to collaborate with industry partners on projects using these mouse models to (i) develop therapeutic vaccines to treat HBV, and (ii) identify therapeutic candidates for treating HBV infection by modulating novel targets identified by the investigators and through the discovery of additional clinically relevant targets.
hepatitis B virus, vaccine, drug discovery, collaboration, partnership, in vivo model, mouse model, preclinical testing