Determinants of Hepatitis B and delta viral host tropism and pathogenesis

Abstract

Hepatitis B virus (HBV) is an ancient virus that has been one of the most

persistent and successful in human history. Globally, two billion people have been

infected with HBV, with approximately 257 million becoming chronically infected,

resulting in around one million deaths a year. Of these chronic HBV carriers, an

estimated 15-70 million are co-infected with hepatitis delta virus (HDV), a satellite virus

that requires an HBV co-infection as it utilizes the HBV envelope proteins for virion

packaging. HBV/HDV co-infections are the most severe form of viral hepatitis. Although

there is an efficacious vaccine that protects against infection with both viruses and antiviral

treatments that are able to suppress viremia and extend a patient’s life, there is no

cure. As such, the global health burden is enormous, with an estimated cost upwards of

$20 billion a year.

A major hinderance to finding a curative therapy is the limited cellular and host

tropism of HBV and HDV as they only robustly infect human and chimpanzee

hepatocytes. There is a lack of in vitro culturing systems that can faithfully recapitulate

the complex biology of the human liver. In addition, with the moratorium on the use of

chimpanzees for federally funded research, there is a dearth of animal models to study

HBV and HBV/HDV infections. Novel in vitro culture systems and small animal models

are thus desperately needed in order to propel the HBV field forward to understand

more about these mysterious viruses and to work towards curative therapies.

My thesis work has focused on developing both novel in vitro and in vivo platforms to

learn more about the viral life cycle and the host response to infection. I have taken an

approach of either adapting non-permissive hosts in order to make them susceptible to

HBV and/or HBV/HDV infection or to adapt the virus to infect previously non-permissive

hosts. These tools are in and of themselves useful but I went beyond just development

and utilized them to gain new insights into the host factors responsible for these viruses’

limited tropism, viral pathogenesis and, most importantly, the host response to infection.