Trends in Microbiology
ReviewMechanisms of Hepatitis B Virus Persistence
Section snippets
HBV Infection and Persistence
HBV is a hepatotropic virus that can cause severe liver diseases, including acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Globally, there are approximately 250 million people suffering from chronic HBV infection, resulting in nearly one million deaths annually [1]. Most chronic HBV carriers acquired the virus from their carrier mothers early in life. In contrast to this vertical transmission (see Glossary), which usually leads to chronic infection, horizontal
HBV Genome and Life Cycle
HBV is an enveloped virus with a circular and partially double-stranded DNA genome of approximate 3.2 kb. After the infection of hepatocytes, the HBV genome is delivered into the nucleus where it is repaired to form covalently closed circular DNA (cccDNA), which then serves as the template to direct viral RNA transcription [5]. The cccDNA is highly stable in the nucleus of infected hepatocytes, and that is the reason why chronic HBV infection is difficult to treat, as cessation of treatment
Interactions between HBV, Pattern-Recognition Receptors and Interferon Signaling
HBV was thought to be a stealth virus [17], as previous studies of patients with acute HBV infection indicated that its infection induced little type I interferon (IFN) immune response [18]. Similar to this observation, when the expression profiles of immune-response genes in the liver of chimpanzees infected by HBV were analyzed [19], no specific induction of IFN-stimulated genes (ISGs) was detected. In agreement with these findings, in a separate experiment using uPA-SCID mice grafted with
Suppression of Host Immunity by HBsAg
HBsAg has immunosuppressive functions and its high level in serum has also been suspected to cause T cell exhaustion [41]. Dendritic cells (DCs), which play an important role in the induction of T cell responses, are functionally impaired in chronic HBV patients [42]. Myeloid DCs (mDCs) treated with HBsAg displayed a tolerogenic phenotype with a decreased T cell stimulatory capacity as well as reduced interleukin-12 (IL-12) production [43]. HBsAg can also bind to monocytes/macrophages and
Impact of Viral Load on HBV Persistence
The ability of HBV to establish persistence is also affected by the size of the viral inoculum. By using chimpanzees as a model, it was demonstrated that the infection of chimpanzees with a low-dose inoculum of 100 or 101 genome-equivalent (GE) of HBV would lead to massive spread of the virus to 100% of hepatocytes and viral persistence [46]. The infection of chimpanzees with 1010 GE of HBV led to massive spread of the virus in the liver and the delayed clearance of the virus. In contrast, the
Age-Dependent Immune Response to HBV Infection
As mentioned above, people who are exposed to HBV via horizontal transmission would often develop self-limited acute infection. In contrast, people who acquired the virus from their mothers via vertical transmission would frequently become chronic HBV carriers. As horizontal transmission usually occurs between adults, and vertical transmission occurs early in life, it was conceivable that this difference in the infection outcome might be due to the difference in immunity between adults and
Maternal Effect on HBV Persistence
Although age may affect the host immune responses to HBV and render small children more susceptible to HBV persistence, recent studies indicated another important factor for HBV persistence. This factor is the effect exerted by HBV carrier mothers on the immune system of their offspring [57]. By crossing female hemizygous HBV transgenic mice to naive male mice, HBV-negative mouse pups were produced. When the 1.3mer HBV genomic DNA was introduced into the liver of these mice at 9 weeks of age
Concluding Remarks
HBV establishes chronic infection in approximately 250 million people worldwide. The research in recent years has generated a significant amount of information for understanding how HBV evades host immunity to establish persistence. HBV can harness type I IFN responses and suppress NK cells to enhance its own replication. It can also take advantage of the developing immune system of young children and the gut microbiota as well as educate fetal immunity to facilitate its persistence in patients
Glossary
- Gut microbiota
- community of microorganisms living in digestive tracts.
- HBeAg seroconversion
- serological change from HBeAg-positive to anti-HBeAg antibody-positive during chronic HBV infection.
- Horizontal transmission
- transmission of the virus between two individuals, usually between adults.
- Hydrodynamic injection
- injection of a high volume of saline via the tail vein of mice within a short duration of 5–8 s.
- Kupffer cells
- resident macrophages of the liver.
- T cell exhaustion
- the progressive loss of T cell
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