New Findings

1.    Potential for AAV as a vector for Hemophilia A gene therapy

    Adeno-associated virus has been a candidate virus for vector gene therapy for many years for several reasons.  First, it is not associated with any human diseases.   Cells carrying provirus precursor don't express new cell surface antigens, so immunogenicity is also minimized.  Finally, experiments have shown that AAV has the potential for long-term transgene expression from both integrated and episomal forms.
    Recently, AAV utility as a viral delivery system in long-term gene expression of coagulation factor IX has been demonstrated in vivo.  Now, Gnatenko, et al, have successfully packaged B-domain deleted fVIII into an adeno-associated viral vector, with detectable secretion of functionally active factor VIII in vitro.  This finding provides the first evidence that AAV is an adaptable virus for fVIII delivery, and given its potential as a
recombinant viral vector and its recent success in factor IX delivery in vivo, it provides a new approach toward hemophilia A.

see reference #1

2.    Parvovirus B19 Associated acute cerebellar ataxia

    PVB19 has been known to cause such CNS diseases as meningitis and encephalitis, but PVB19-associated acute cerebellar ataxia had never been reported.  Last year, however, a two year old boy was diagnosed with acute cerebellar ataxia.  He was seroposititve for IgM and IgG antibodies against PVB19 but he tested negative for antibodies in the cerebral spinal fluid (CSF).  Similarly, PCR tests were positive for PVB19 in the blood serum but not in the CSF.  Because acute cerebellar ataxia is a disease of the central nervous system, and because tests showed that PVB19 had not infected the cells of the nervous system, it is probable that PVB19-associated acute cerebellar ataxia does not involve direct viral invasion.  One possible mechanism is that it is a post infectious allergic reaction.

see reference #2

3.    Role of PVB19 in Pathogenesis of Giant Cell Arteritis

    Recent findings suggest that PVB19 may play a role in the pathogenesis of Giant Cell Arteritis (GCA).  GCA is a systemic vasculitis of unknown etiology that involves large and medium sized vessels.  Study of the possible association between PVB19 and GCA was motivated by several factors, including: 1-B19 was been shown to occur in epidemic cycles like those of GCA, 2-B19 has been associated with other forms of systemic vasculitis, 3-that B19 is capable of persistent and recurrent infection, and 4-that it appears to be associated with inflammatory rheumatic disease.
    The study found that there was a highly significant correlation between the presence of B19 in DNA (as evidenced by PCR analysis) and histological evidence of GCA, including symptoms of systemic vasculitis and inflammatory arthritis.  This correlation is based on the demonstration of B19 DNA in the involved tissue and on the recent finding that the cellular receptor for B19 is also expressed on endothelial cells.  It is possible that the correlation is not etiologic, however, and further research is necessary to confirm these findings.

see reference #3

4.    Fetal Hematological Parameters for Fetal PVB19 Infection Prognosis

    Fetal parvovirus B19 infection causes fetal anemia, non immune hydrops foetalis and fetal thrombocytopenia, which in severe cases can lead to birth defects or death of the fetus.  Although detection of fetal PVB19 infection is easily obtained by PCR analysis of amniotic fluid, there is presently no way of predicting which cases will lead to severe outcomes, such as birth malformations and death.  Additionally, intrauterine transfusions have been shown to be an effective treatment in only some cases.  Attempts have recently been made to use fetal hematological parameters, such as the severity of the fetal anemia, to develop parameters that will help predict the outcome of the infection and to give insight as to when blood transfusions will be an effective treatment.
    So far, there has been no success in developing such parameters.  In a recent study, the severity of anemia of the fetuses who died was similar to that of the fetuses who had favorable outcomes.

see reference #4

5.    Risk Factors for PVB19 Infection in Pregnancy
    PVB19 infection during pregnancy greatly increases a woman's risk of fetal death.  Thus, recent studies have attempted to determine the risk factors for PVB19 infections and to quantify the importance of previously hypothesized risk factors for infection, including family structure, housing density, length and type of education, and socioeconomic status.  PVB19 infection is transmitted primarily though respiratory secretions, so study of contact patterns in outlining the risk factors for PVB19 infection are especially important.  One study in Denmark attempted to outline the risk factors for both past and acute PVB19 infection.
    In terms of risk factors for past and acute infection, the Denmark study found that women with many siblings and an interval to the nearest sibling of less than two years were more likely to have been infected as children.  Also, the number of children already born in the household increased the pregnant woman's risk of both past and acute infection.  Finally, pregnant women with children aged 5-7 years were at the greatest risk, which is consistent with the theory that children during early school years represent a particularly great risk for infection.  The intensity of child exposure in the woman's workplace is another risk factor for acute and past infection, with school teachers and after-school-club personnel being at highest risk.  Contrary to previous beliefs, socioeconomic factors, such as household crowding, did not pose as a significant risk factor.  In general, susceptible pregnant women are at highest risk of PVB19 infection during epidemics, especially if she has a high level of contact with children.

see reference #5

6.    Involvement of PVB19 in Acute Fulminant Liver Failure
    Recent studies are investigating the possible involvement of parvovirus B19 infection in liver injury.  Previous detection of PVB19 DNA in livers from patients requiring transplantation for acute fulminant liver failure (AFLF) of unknown etiology suggested the possibility that PVB19 infection plays a role in the development of the disease.  The presence of globoside, the B19 receptor, on human liver cells also supports the hypothesis that PVB19 could be infecting liver cells.  A recent study used immune adherence PCR to detect the presence of B19 virions in liver cells of patients with AFLLF.  This finding, together with the PCR analysis detecting viral mRNA encoding the structural capsid protein in liver tissue, argue strongly for the involvement of B19 virus in the development of acute fulminant liver failure.

see reference #6

7.    Role of PVB19 in Systemic Sclerosis
    Recent studies suggest that PVB19 infection of bone marrow cells may be involved in the development of systemic sclerosis (SSc), a connective tissue disease characterized by skin and visceral organ involvement.  Preliminary observations detected the presence of B19 viremia in 4% of SSc patients, compared to a rate of 0.6% in healthy blood donors.  Also, the presence of anti-B19 IgG, but not anti-B19 IgM, in the serum of B19 DNA positive  SSc patients suggest a persistent PVB19 infection.  Now, a more recent study has discovered the presence of B19 infection in bone marrow from a significant percentage of SSc patients compared with that of a control group.  Although these preliminary observations suggest a possible role of B19 infection in SSc, further studies are necessary to confirm the hypothesis.

see reference #7

8.    PVB19-Associated Disease in Bone Marrow Transplantation
    Recent studies suggest that PVB19 can persist in immunocompromised patients and produce severe clinical illness.  A retrospective study was recently undertaken to evaluate the incidence of parvovirus B19-associated infections in bone marrow transplant patients and its impact on transplant related morbidity and mortality.  PCR analyses of blood and tissue specimens of patients who had developed infections or complications after a bone marrow graft tested positive for B19 infection a significant percentage of the time.  This finding suggests that parvovirus B19-associated infections are more common in immunocompromised patients (such as those receiving bone marrow transplants) than was previously anticipated.

see reference #8

9.    Progress in Adeno-Associated Virus Type-2 Vector Production
    Although vectors derived from human parvovirus AAV-2 are among the most promising gene delivery vector vehicles currently being developed, they have the drawback that they are limited in their clinical application due to the laborious work required to prepare high titer and pure AAV-2 stocks.  Recent improvements to the basic manufacturing protocol, however, is resulting in the production of significantly higher quality and quantity of viral stocks.  New techniques include: 1-modification of conventional transfection/infection protocols, 2-development of helper virus-free vector production, and 3-use of vector producer cell lines.  Future techniques may utilize a combination of these techniques for rAAV manufacturing.  While each of the strategies have many benefits, each one also has a number of drawbacks that may still complicate the use of large-scale AAV-2 vector manufacturing.  Further research and will be required for the development of an ideal AAV-2 vector production method that is fully suitable to clinical requirements.

see reference #9

10.     Viral  Safety of SD-Treated Plasma
    Solvent/detergent (SD) treatment of plasma and plasma proteins is highly efficient in inactivating lipid-enveloped viruses.  Non-lipid-enveloped viruses like parvovirus B19, on the other hand, are not effected by SD-treatment of plasma.  PVB19 is a blood-borne pathogen, and there is thus a great risk of infection involved when blood transfusions are given.  A recent study in Norway, however, showed that in populations where B19 is endemic, an epidemiological equilibrium exists such that specific viral  antibodies against PVB19 are present in the plasma and that they serve to neutralize the B19 viral particles that may be present.  Thus, although the SD-treated plasma itself does nothing to affect PVB19, the SD-treated plasma is nonetheless safe with respect to transmission of infection with B19 in areas where B19 is endemic.

see reference #10


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