Megha Mathakia

DENSOVIRINAE

• Densovirus
• Iteravirus
• Contravirus
  The Densovirus subfamily is associated with just insect hosts.

PARVOVIRINAE

• Parvovirus
• Erythrovirus
• Dependovirus
  The Parvovirus subfamily is associated with mainly warm-blooded animal hosts. Of these, the RA-1 virus of the parvovirus genus, the B19 virus of the erythrovirus genus, and the adeno-associated viruses (AAV) 1-5 of the dependovirus genus are human viruses.

HISTORY

Parvoviruses are among the smallest and simplest eukaryotic viruses and were only discovered in the 1960's. Although known to be widespread in many organisms in nature, the first human parvovirus infections were discovered only in the last few decades. Unfortunately, the pathogenic human parvoviruses do not grow in culture and are therefore not very well understood.

The first human parvovirus that was discovered was the B19 parvovirus. This virus was discovered by a virologist named Yvonne Cossart in London in the 1970šs while investigating laboratory assays for hepatitis B. Using an immunoelectrophoretic technique, Cossart reacted sera from blood bank donors (antigen source) with samples from hepatitis patients (antibody source). When results form these tests were compared with those from more specific assays, she noticed a series of "false positive" reactions, which, when investigated further, showed particles that appeared to be parvoviruses. In fact, the name of the parvovirus B19 was derived from the patient code of one of the viremic blood bank donors. A few years later, the virus was linked with fifth disease, a common rash childhood illness.

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MORPHOLOGY

The icosahedral parvovirus particles contain just protein and DNA genome. The three capsid proteins are VP1, VP2, and VP3. Together, the capsid confers much stability upon the virus particles, allowing for resistance to inactivation by pH, solvents, or temperatures up to 50 degrees C. Parvoviruses are thus among the most resistant viruses known.

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GENOME

Parvovirus genome is linear, monopartite, ss DNA of approximately 5 kb in size. Most of the packaged strands of DNA are minus-sense, but the adeno-associated viruses package equal amounts of plus and minus sense DNA. The genome also has palindromic sequences at both the 3' and 5' ends which can fold back on themselves to form "hairpin" structures that are stabilized by self-hydrogen bonding. These "hairpin" structures are critical for genome replication.

Parvovirus replication and assembly occurs in the nucleus and is dependent upon host cellular functions. The mechanism of replication of the genome is unique to the virus family. The hairpin structure at the 3' end is used as a self-primer to start synthesis of a plus-sense DNA, resulting in double stranded-DNA. The hairpin structure is then again used as a primer to transcribe more minus-sense strands from the ds DNA. The current model proposes that the growing strand replicates back on itself to produce a tetrameric form which is then cleaved to result in two plus-sense and two minus-sense strands of DNA.

For more on replication click here.

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HUMAN VIRUSES and DISEASES

• The RA-1 virus has been associated with rheumatoid arthritis.

• The adeno-associated viruses (AAV's 1-5) have not been established to cause any disease, however, with coinfection with a helper virus (either adenovirus or a herpesvirus) results in host cell infection. Because of this lack of association with any known human disease and because of the simplicity of the genome and the ease with which it can integrate into host genome, AAV's recently have received much attention as possible vectors for gene therapy.
  ADENO-ASSOCIATED VIRUS
  
  From Virus Morphology
  © 1988 Churchilll Livingstone

• Parvovirus B19 has been associated with diseases such as arthritis, aplastic crisis in chronic hemolytic anemia, chronic anemia in immunodeficiency syndromes, and hydrops fetalis. However, B19 is most commonly associated with the disease erythema infectiosum (EI), also known as fifth disease.
  PARVOVIRUS B19
  
  From Virus Morphology
  © 1988 Churchilll Livingstone

  Fifth disease is a mild childhood illness characterized by a facial rash, known as "slapped cheek," as seen below.

  "SLAPPED CHEEK"
  
  From Biotrin International
  http://www.biotrin.ie/

  Also seen are lace-like or reticulated rashes on the trunk and extremities. Rashes are usually fleeting, typically disappearing within a couple of days. However, reappearance of these rashes may be seen up to several weeks following infection with the virus in response to changes in stimuli such as temperature, sunlight, and emotional stress. Asymptomatic infection with B19 has been reported in about 20% of cases.

  For more information on fifth disease click here.

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EPIDEMIOLOGY and TRANSMISSION

B19 is extremely contagious, and infection occurs worldwide and can occur throughout the year, in people of all ages, either in epidemics or as sporadic cases. However, infection is most frequently recognized during outbreaks of EI in schools. These outbreaks usually begin in late winter or early spring and may continue until school is out for the summer. Seropositivity rates increase with age, with over 50% of adults being seropositive and immune.

Studies indicate that the incubation period for clinical EI can range from 4 to 20 days, with the appearance of rash averaging 17 to 18 days. It is believed that transmission usually occurs during this incubation period.

The normal mode of B19 transmission is by droplet infection or from person-to-person through direct contact with respiratory secretions. B19 levels in saliva have been shown to be comparable with those levels found in blood. A second route of transmission that is possible for the virus is transplacental. About 30% of mothers who are primarily infected pass on the virus to the fetus, but this is usually not harmful to the fetus. Transmission is also possible through blood and blood products, but screening is not done for this virus because of its rarity of transmission via this route and relative harmlessness.

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PATHOGENESIS

B19 virus can be detected in both blood and respiratory secretions five to seven days before a rash is developed and before antibodies can be detected in serum. The virus targets erythroid progenitor cells in the bone marrow and spleen, which, when infected, undergo lysis. There is a resulting decline in the erythrocyte count as well as in lymphocyte, granulocyte, and platelet counts.

After the virus's incubation period, a fever may start, and a few days later, a rash may develop. The rash is believed to me an immune response because, simultaneously, B19-specific IgM antibodies can be detected in the host. B19-specific IgG antibodies can be detected a few days later. Also, the patient is no longer infectious a few days after the rash develops. Those persons without the blood group P antigen are naturally resistant to infection with B19 because it is its natural receptor. However, this occurrence is quite rare.

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DIAGNOSIS

Although parvovirus infection can be quite apparent clinically, the virus's inability to grow in standard cell culture systems has made widespread laboratory testing of B19 quite difficult. Right now, the most sensitive test to detect recent infection is the IgM-antibody assay. Through either enzyme immunoassay (EIA) or radio immunoassay (RIA), antibodies can be detected in about 90% of cases by the third day after the onset of symptoms. In addition, tests can also be done to test for the presence of viral DNA. Currently, the most sensitive test for detecting the virus is nucleic acid hybridization. These tests have suggested that B19 DNA was more likely to be present in leukocytes than in serum.

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MANAGEMENT and THERAPY

Currently there is no vaccine to prevent infection with B19, but recently a cell line that expresses the virus's capsid proteins as noninfectious viruslike particles has been proposed as a source of antigen in development of a vaccine. No studies have yet been done as to the effectiveness of passive prophylaxis with immune globulins.

The treatments for the diseases, which include antivirals and normal human immunoglobulin are generally for relief of symptoms only. Immunoglobulin preparations are a good source of neutralizing antibodies because most of the adult population has been exposed to the B19 virus. These treatments are usually only given to pregnant nonimmune women, immunocompromised individuals, and those with chronic hemolytic anemia because these groups are at the highest risk of complicated parvovirus infections. Studies have indicated that relapse of the virus may be prevented by regular IgG infusions.

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PREGNANT WOMEN

Infection with parvovirus B19 is generally asymptomatic in pregnant women and most will deliver a normal child at term, but there is still substantial risk of transplacental virus tranmission and subsequent fetal infection. Many women who were infected with the virus just a few weeks before delivery have delivered fetuses who have died from hydrops fetalis. Hydrops fetalis is marked by edema, which is believed to be the result of severe anemia and congestive heart failure brought on by the B19 virus. This risk has created a great deal of concern among health-care providers, public health officials, and pregnant women. As a result, women with a documented infection have been closely monitored through serum ga-fecoprotein level testing and diagnostic ultrasound examinations.

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USEFUL WEB LINKS

The CDC's Page on Parvoviruses

Biotrin International

Biotrin's Parvovirus B19 Booklet

AJC's Parvovirus Page

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REFERENCES

Books
• Fields, Bernard. Virology, 3rd ed. Philadelphia: Lippincott-Raven, 1996.
• White, David and Frank Fenner. Medical Virology, 4th ed. San Diego: Academic Press, 1994.

  Journals

• Anderson, MJ, et al. "Human parvovirus, the cause of erythema infectiosum (fifth disease?)," Lancet 1983; 1; 1378.

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