Hepatitis B Virus

Family: Orthohepadanviridae

Genus: Orthohepadnavirus

Introduction

• Spherical, enveloped virus with icosahedral capsid, 42nm in diameter.
• it is DNA virus (partially double stranded ) and forms a circle of around 3-2 kb.
• the full length of DNA minus strand ( L or long strand) id complementary to all HBV mRNAs.
• the positive strand (S or Short strand) is variable and between 50-80% of the unit length.
• there are 4 open reading frames that encode 7 polypeptides.
• Hepatitis B is a viral infection that attacks the liver and can cause both acute and chronic disease.
• The virus can get transmitted from person to person through contact with the blood or other body fluids of an infected person.

• these include structural proteins of the virion surface and core, a small transcriptional factor (x) and a large polymerase (p) proteins that include DNA polymerase, reverse transcriptase, and RNase H.
• The S gene has 3 in-frame initiation codons and encodes the major HBsAg as well as polypeptides in addition pre-S2 or pre- S1 and Pre- S2 sequences.
• the C gene has 2 in frames initiation codons and encodes HBcAg plus HBe protein, which is processed to produce soluble HBeAg.
• there is 3 morphologically distinct form of HBV. They are Dane particle, filamentous particle, and Spherical particle.

• Small, 20nm spherical or 200nm tubular form comprises of virus surface proteins, which are synthesized in excess of 42nm complete virions.
• 27nm nucleocapsid, it comprises of theDNA genome surrounded by HBcAg.
• HBeAg is also found in the soluble form in virus positive sera and is related to the core antigen.

• The virus is stable to organic solvent and resistant to heat and PH.
• Replication of HBV involves reverse transcriptase.
• there is one dominant neutralizing epitope (HBcAg). Antibodies against one strain by HBV with protecting against all strains.
• there are multiple serotypes of HBV, resulting from variation in 2 minor epitopes.

HBV antigens

HBsAg

• surface antigen encodes by S gene region.
• a major component of envelope present in the blood stream during acute infection and carrier stage.
• four phenotypes of HBsAg have been recognized: adw, adr, ayw, and ayr.

HBcAg

• core antigen and antibody against HBcAg will not confer immunity because HbcAg is not exposed on the surface of the virion.

HBeAg

• it is an antigen associated with the core and assembled into progeny virus.
• if it is generated from core protein by proteolytic cleavage of other antigens.

HBx protein

• the exact function of this protein is unknown.
• This protein has been detected with other proteins.

HBV genotypes

• HBV DNA can be detected in the bloodstream one week after the infection.
• The detection of HBV DNA in blood indicates the virus is replicating capacity
• HBV DNA polymerase can also be detected as HBV DNA.
• It can be used as an indication of disease progression for therapy .
• The hepatitis B virus can survive outside the body for at least 7 days.
• A person who is not protected by the vaccine may get an infection.
• The incubation period of the hepatitis B virus is 75 days on average,
• The virus can persist and develop into chronic hepatitis B.
• In highly endemic areas, hepatitis B is most commonly spread from mother to child at birth.
• The development of chronic infection is very common in infants infected from their mothers.
• Hepatitis B is also spread by mucosal exposure to infected blood and various body fluids such as saliva, menstrual, vaginal, and seminal fluids.
• Sexual transmission of hepatitis B may occur, particularly in unvaccinated men.
• Transmission of the virus may also occur through the reuse of needles or among persons who inject drugs

HBV has been classified into 8 genotypes: A-H

• Genotype A- USA, Africa
• Genotype B- USA, Africa
• Genotype C- USA, Asia
• Genotype D- Russia
• Genotype E- Russia
• Genotype F- South Asia, Alaska
• Genotype G- Unknown
• Genotype H- Unknown

HBV has a single tropism for hepatocytes. HBV transcription has properties that help to explain its tropism for liver cells.

• HBV encodes two enhancer elements that have binding sites for host transcription factors uniquely enriched in liver cells.
• In addition to expressing 5 mRNA (for making HBsAg-S, HBsAg- M, HBsAg-L, HBeAg and a protein called x). HBV makes a sixth, longer transcript called the pregenomic RNA (pgRNA).
• Following its synthesis, pg RNA is transported to the cytoplasm, where it performs and functions:
• It serves as mRNA for translation of the remaining viral proteins (core and pol), and
• As a template for viral genome synthesis

Pathogenesis

• Following infection, the virus enters the hepatocytes via blood.
• Immune response (cytotoxic T cells) to viral antigens expressed on liver cells surface contribute to clinical syndrome.
• If the liver injury is very mild (mild CTL response) some patients remain asymptomatic. However, those with more robust CTL responses develop signs and a symptom of liver injury, the stages is called acute hepatitis.
• In 95% cases, the immune response is sufficient to clear an infection. In those cases viral gene products in the blood decline precipitously, and anti- HBsIgG clear virus and provide protective immunity against reinfection.
• In 5% cases, there have little or no free circulating anti-HBsIgG, leading to chronic infection. The persistence of HBsAg in the blood for 6 months or more confirms chronic infection.
• Once the chronic infection is established, the patient is likely to suffer from sporadic episodes of active hepatitis associated with liver cell death, which is readily demonstrated by high serum aminotransferase level.
• After many years of persistent infection and associated scarring of the liver, some patients progress to cirrhosis, a potentially fatal condition.
• After 2-4 decade of chronic infection, the risk of developing hepatocellular carcinoma (HCC) is increased. 100- Folds.
• The rate of HCC is higher in chronic carriers, especially in those who are “e” antigen positive.
• Anti- HBs antibody confers lifelong immunity (anti- HBsIgG)
• Anti- HBe antibody indicates low transmissibility.

Infective materials and transmission

• Hepatitis B is transmitted by the exchange of body fluids.
• Blood, serum, breast milk and in some instances saliva.
• A person, most at risk include I.V drug users, who share needles and syringes.
• Health care workers in contact with potentially contaminated blood or body fluids.
• Babies born to mothers with the virus
• Anyone in inanimate contact with an infective person.

Transmission

• Most often by the parenteral route.
• Sexual contact
• Recent studies (in Nepal context), have shown that maternofoetal transmission and transmission via milk are quite insignificant compared to the formers mode of spread.

Host factors

• In countries with uncommon infection, the most common group of people to be infected with the HBV id found to be within 20-30 years of age.
• Countries with higher prevalence, however, show higher rates among teenagers and infants as well.

Symptoms

• Some people have an acute illness with symptoms that last for several weeks such as yellowing of the skin and eyes, dark urine, vomiting, extreme fatigue, nausea, and abdominal pain.
• In few case, persons with acute hepatitis can develop acute liver failure which can lead to death.
• Additionally, In some people, the hepatitis B virus can also cause a chronic liver infection that can later develop into cirrhosis of the liver or liver cancer.

Major risk group

• blood recipients
• unprotected sex- sex workers
• infecting drug users
• mother to child
• others: ear/Nose piercing, dental procedure
• more than 250 million carriers; 1 million deaths per year.

REFERENCE

Cheesbrough, M.Medical Laboratory Manual for Tropical Countries.Vol. Vol 2. ELBS London, 2007.

Tille, P.Diagnostic Microbiology.13th. Elsevier, 2014.

D, Grenwood, Slack RCB, and Peutherer J.Medical Microbiology.Dunclude Livingstone: ELBS, 2001.