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Hepadnaviruses: Hepatitis B Virus and Hepatitis D Virus  
  
3425   11:39 صباحاً   date: 19-11-2015
Author : Kayser, F. H
Book or Source : Medical Microbiology
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Date: 19-11-2015 1601
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Hepadnaviruses: Hepatitis B Virus and Hepatitis D Virus

 

A hepatitis B virus (HBV) infection of the liver cells results in expression of viral antigen on the cell surface, followed by im­munological cell damage with acute, possibly fulminant, chronic persistent or chronic aggressive hepatitis. The final stages can be liver cirrhosis or hepa­tocellular carcinoma. A concurrent or later superinfection by a defective, RNA-containing and HBV-dependent hepatitis D virus (HDV, delta agent) normally exacerbates the clinical course. Both viruses are transmitted in blood or body fluids, whereby even a tiny amount of blood may be enough to cause an infection.

Diagnosis: immunological antigen or antibody assay in patient serum. The antigen or antibody patterns observed provide insights on the stage and course of the disease.

Prevention: active immunization with HBV surface (HBs) antigen; concur­rent postexposure passive immunization.  

Hepatitis B pathogen. The hepatitis B virus (HBV) is the main representative of the family of hepadnaviruses, Hepadnaviridae. The name of the family is an acronym of the disease caused by the virus and its genomic type. It causes a sometimes chronic form of liver inflammation (hepatitis) and its genome consists of partially double-stranded DNA (hepadnavirus = hepatitis DNA virus). The replication cycle of the HBV includes a transient RNA phase. The HBV possess an envelope made up of a cellular double lipid layer in which are integrated the hepatitis B surface (HBs) antigen, a 25 kDa polypeptide, and its precursor stages PreSl (40 kDa) and PreS2 (33 kDa). (Fig. 1). This envelope encloses the actual capsid, which consists of the hepatitis B core (HBc) antigen with 21 kDa and contains the genome together with the DNA polymerase. The complete, infectious virion, also known as a Dane particle after its discoverer, has a diameter of 42 nm, the inner structure 27 nm. The virus replicates in liver cells. The Dane particles and the HBs antigen, but not the HBc antigen, are released into the bloodstream, whereby the HBs antigen is present in two different forms, a filamentous particle approximately 22 x 100 nm and a spherical form with a diameter of about 22 nm. A further viral protein is the HBe antigen, which represents a posttranslational, truncated form of the HBc antigen and is no longer capable of spontaneous capsid for­mation. It is also released from the hepatic cells into the blood.

Fig. 1 The capsid, which consists of Hbc and Hbe antigens, encloses the en­tire DNA antisense strand, the incom­plete sense strand, and the reverse tran­scriptase (not shown here). The enve­lope contains the three forms of the Hbs antigen: PreS1 = complete protein, PreS2 = shortened form of PreS1, HBs antigen = HB surface antigen in the proper sense, shortened form of PreS2.

Hepatitis D pathogen. A certain percentage of HBV-infected persons, which varies geographically, are also infected by a second hepatitis virus discovered at the end of the seventies in Italy, the delta agent or hepatitis D virus (HDV). It was originally thought to be a new HBV antigen. In fact, it is an unclassified RNA virus that codes for the delta antigen. Its capsid consists of HBs antigen, i.e., HBV-coded material. For this reason, the virus can only replicate in per­sons infected with HBV (in this case the “helper virus”).

The delta agent is 36 nm in size and possesses a very short viral RNA con­taining 1683 nucleotides. This RNA is circular, has antisense (minus) polarity and is reminiscent in size and structure of the RNA in plant viroids. Its transcription and replication take place in the cell nucleus by means of a cellular polymerase. The resulting RNA sense strand contains, in contrast to viroids, a protein-coding segment comprising about 800 nucleotides, which the cell processes into an mRNA. The HDV codes for two proteins with 27 and 29 kDa (delta antigen). The shorter protein with 195 amino acids, which pro­motes RNA replication, is produced earlier in the replication cycle. Later, after the stop codon UAG of the mRNA has been transformed (enzymatically?) into UGG, the longer protein with 214 amino acids is synthesized; it inhibits rep­lication and controls the encapsidation of the HDV RNA in the HBs antigen.

Pathogenesis and clinical picture. The incubation period of hepatitis B is four to 12 weeks, followed by the acute infection phase, icteric, or anicteric course, once again with a variable duration of two to 12 weeks. The hepatic cell damage resulting from an HBV infection is not primarily due to cytopathic activity of the virus, but rather to a humoral and cellular immune response directed against the virus-induced membrane antigens (HBs, HBc) on the surface of the infected hepatocytes: 0.5-1% of those infected experience a fulminant, often lethal, hepatitis. In 80-90% of cases the infection runs a be­nign course with complete recovery and elimination of the HBV from the body. A chronic infection develops in 5-10%. Three forms are differentiated, but mixed forms are possible:

-healthy HBV carriers,

-chronic persistent hepatitis (CPH) without viral replication, and finally

-chronic aggressive hepatitis (CAH) with viral replication and a progressive course.

A chronic infection can result in development of a carcinoma (hepatocellular carcinoma, HCC) or cirrhosis of the liver, with incidence varying widely from one geographic area to another. The delta agent appears to have an unfa­vorable influence on the clinical course, usually making the disease more aggressive, increasing the number of complications and worsening the prog­nosis.

Diagnosis. Hepatitis B is diagnosed by identifying the various HBV antigens or the antibodies directed against them. Both antigens and antibodies can be detected in patient blood using a solid phase test (enzyme immunoassay). The individual components manifest in specific patterns. Fig. 2 shows the sequence of phases in an uncomplicated hepatitis B infection, upon which the guiding principles in laboratory diagnosis of HBV infections are based (Table 1).

The hepatitis D virus is diagnosed by detection of delta antigen or possibly antibodies to delta (IgM) in the blood.

Fig. 2 Typical antigen and antibody concentration curves after infection.

Tab. 1 Laboratory Diagnostics in HBV Infections

Epidemiology and prevention. Humans are the sole reservoir of HBV. Trans­mission is parenteral, either with blood or body fluids containing HBV (sexual intercourse) that come into contact with mucosa, lesions, or microlesions in the skin. In transmission by blood, the tiniest amounts contaminating syringe needles, ear-piercing needles, tattooing instruments, etc. suffice to produce an infection. Hepatitis B infections from blood transfusions have been greatly reduced by thorough screening of blood donors for HBs antigens, despite which patients receiving multiple transfusions or dialysis remain a high- risk group.

Another high-risk group includes all healthcare workers with regular blood contact. All blood samples must be considered potentially infectious and handled only with disposable gloves. Addicts who inject drugs with nee­dles are also obviously exposed to a very high level of risk.

Since no effective chemotherapy against HBV has been developed to date, the WHO recommends general hepatitis B prophylaxis in the form of active immunization with HBs antigen. In response to a sudden high-level infection risk (accidental inoculation with infectious material), persons whose im­mune status is uncertain should also be passively immunized with human anti-HBs antiserum—if possible within hours of pathogen contact.

It has not yet proved feasible to grow HBV in vitro. The antigen used in vaccinations can be isolated from human blood. Fear of AIDS infections has resulted in emotionally based, unjustifiable rejection of this vaccine. An alternative vaccine is now available based on developments in genetic en­gineering: the HBs antigen can now be synthesized by a yeast fungus.

Prevention: hepatitis B booster vaccines. Periodic booster shots, especially for persons at high risk, were recommended for some time to maintain suffi­cient immune protection. However, since all successfully vaccinated persons build up immunity rapidly following renewed contact with the pathogen (“immunological memory,”), this recommendation has been re­placed in a number of countries by the following scheme:

Following immunization on the classic model (0,1, and 6 months), the anti-HBs antibody titer is measured within one to three months. Responders (titer 100 IU/l) require no booster. In hyporesponders and nonresponders (titer <100 IU/l), an attempt should be made to reach a titer of 100 1U/1 with a maximum of three further vaccinations.

References

Fritz H. Kayser, M.D. Emeritus Professor of Medical Microbiology Institute of Medical Microbiology, University of Zurich, Zurich, SwitzerlandThieme 2005, Stuttgart ! New York.




علم الأحياء المجهرية هو العلم الذي يختص بدراسة الأحياء الدقيقة من حيث الحجم والتي لا يمكن مشاهدتها بالعين المجرَّدة. اذ يتعامل مع الأشكال المجهرية من حيث طرق تكاثرها، ووظائف أجزائها ومكوناتها المختلفة، دورها في الطبيعة، والعلاقة المفيدة أو الضارة مع الكائنات الحية - ومنها الإنسان بشكل خاص - كما يدرس استعمالات هذه الكائنات في الصناعة والعلم. وتنقسم هذه الكائنات الدقيقة إلى: بكتيريا وفيروسات وفطريات وطفيليات.



يقوم علم الأحياء الجزيئي بدراسة الأحياء على المستوى الجزيئي، لذلك فهو يتداخل مع كلا من علم الأحياء والكيمياء وبشكل خاص مع علم الكيمياء الحيوية وعلم الوراثة في عدة مناطق وتخصصات. يهتم علم الاحياء الجزيئي بدراسة مختلف العلاقات المتبادلة بين كافة الأنظمة الخلوية وبخاصة العلاقات بين الدنا (DNA) والرنا (RNA) وعملية تصنيع البروتينات إضافة إلى آليات تنظيم هذه العملية وكافة العمليات الحيوية.



علم الوراثة هو أحد فروع علوم الحياة الحديثة الذي يبحث في أسباب التشابه والاختلاف في صفات الأجيال المتعاقبة من الأفراد التي ترتبط فيما بينها بصلة عضوية معينة كما يبحث فيما يؤدي اليه تلك الأسباب من نتائج مع إعطاء تفسير للمسببات ونتائجها. وعلى هذا الأساس فإن دراسة هذا العلم تتطلب الماماً واسعاً وقاعدة راسخة عميقة في شتى مجالات علوم الحياة كعلم الخلية وعلم الهيأة وعلم الأجنة وعلم البيئة والتصنيف والزراعة والطب وعلم البكتريا.