Trends in Microbiology
Volume 26, Issue 1, January 2018, Pages 33-42
Journal home page for Trends in Microbiology

Review
Mechanisms of Hepatitis B Virus Persistence

https://doi.org/10.1016/j.tim.2017.07.006Get rights and content

Trends

HBV frequently causes chronic infection after vertical transmission but mostly self-limited acute infection after horizontal transmission.

HBV harnesses type I interferon immune response to enhance its own replication.

HBV persistence is affected by the age of infection, size of viral inoculum, and gut microbiota.

Maternal HBeAg can train Kupffer cells of the offspring, likely in utero, to suppress HBV-specific CD8+ T cells in the presence of HBeAg after birth.

Hepatitis B virus (HBV) chronically infects 250 million people worldwide, resulting in nearly one million deaths annually. Studies in recent years have significantly improved our knowledge on the mechanisms of HBV persistence. HBV uses multiple pathways to harness host innate immunity to enhance its replication. It can also take advantage of the developing immune system and the not-yet-stabilized gut microbiota of young children to facilitate its persistence, and use maternal viral e antigen to educate immunity of the offspring to support its persistence after vertical transmission. The knowledge gained from these recent studies paves the way for the development of new therapies for the treatment of chronic HBV infection, which has so far been very challenging.

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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