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Renal involvement of human parvovirus B19 in an immunocompetent host.

Human parvovirus B19, which is most commonly known to cause erythema infectiosum in children, is also known to cause infection in adults, with complications ranging from a self-limited polyarthropathy in immunocompetent patients to hydrops fetalis in pregnant women, transient aplastic crises in patients with chronic hemolytic anemias, and chronic aplastic anemia in immunocompromised hosts. We describe a previously healthy immunocompetent woman who presented with manifestations of acute parvovirus B19 infection.

Adult↗

Resolution of chronic parvovirus b19-induced anemia, by use of highly active antiretroviral therapy, in a patient with acquired immunodeficiency syndrome.

We present what is, to our knowledge, the second case report of a patient with acquired immunodeficiency syndrome and transfusion-dependent anemia caused by persistent infection with parvovirus B19. The patient's anemia was successfully treated, and she demonstrated serologic evidence of eradication of parvovirus after having received effective therapy for human immunodeficiency virus infection.

AIDS-Related Opportunistic Infections↗

Papular purpuric rash due to parvovirus B19 with distribution on the distal extremities and the face.

We describe 3 patients who presented with a distinctive clinical picture of the purpuric rash called "gloves-and-socks syndrome" which was characterized by an acral distribution of the rash that involved not only the distal part of the extremities but also the chin and perioral area. Serologic analysis for parvovirus B19 yielded positive results. Parvovirus B19 should be included in the evaluation of febrile purpura.

Adolescent↗

Safety and immunogenicity of a recombinant parvovirus B19 vaccine formulated with MF59C.1.

A recombinant human parvovirus B19 vaccine (MEDI-491; MedImmune) composed of the VP1 and VP2 capsid proteins and formulated with MF59C.1 adjuvant was evaluated in a randomized, double-blind, phase 1 trial. Parvovirus B19-seronegative adults (n=24) received either 2.5 or 25 microg MEDI-491 at 0, 1, and 6 months. MEDI-491 was safe and immunogenic. All volunteers developed neutralizing antibody titers that peaked after the third immunization and were sustained through study day 364.

Adjuvants, Immunologic↗

Parvovirus B19 encephalitis presenting as immune restoration disease after highly active antiretroviral therapy for human immunodeficiency virus infection.

Illness occurring during the initial months of highly active antiretroviral therapy (HAART) for human immunodeficiency virus infection may be a consequence of the restoration of an immune response against opportunistic pathogens (i.e., immune restoration disease [IRD]). We describe a young man who had AIDS complicated by parvovirus B19 infection and RBC aplasia and who developed a painless, progressive dyspraxia of the left arm and an expressive dysphasia 4 weeks after commencing effective HAART. Neuroimaging demonstrated multiple right fronto-parietal lesions, and, following extensive investigations, including a brain biopsy, it was concluded that the brain lesions represented IRD associated with parvovirus B19 infection.

AIDS-Related Opportunistic Infections↗

Single-nucleotide polymorphisms associated with symptomatic infection and differential human gene expression in healthy seropositive persons each implicate the cytoskeleton, integrin signaling, and oncosuppression in the pathogenesis of human parvovirus B19 infection.

This study was undertaken to further examine the role of the host response to parvovirus B19 in the development of symptoms and consequences of viral persistence. Genomic DNA from 42 patients with symptomatic B19 infection was analyzed using the HuSNP assay (Affymetrix), and the results were compared with those from analysis of 53 healthy control individuals. Fifty-seven single-nucleotide polymorphisms were identified that were significantly associated with symptomatic infection. Total RNA from peripheral blood mononuclear cells from 57 B19-seropositive and 13 B19-seronegative donors was analyzed by hybridization to a single-color microarray representing 9522 human genes. Ninety-two genes were shown to be differentially expressed. Differential expression was confirmed in 6 of 38 genes (SKIP, MACF1, SPAG7, FLOT1, c6orf48, and RASSF5) tested using real-time quantitative polymerase chain reaction in a different group of healthy subjects. Genes identified in both studies play a functional role in the cytoskeleton, integrin signaling, and oncosuppression, themes that have been shown to be important in parvovirus infections.

Adolescent↗

A case of persistent parvovirus B19 infection with bilateral cartilaginous and ligamentous damage to the wrists.

We describe a case of persistent parvovirus B19 infection in a 48-year-old female physician that was complicated by prolonged fatigue and arthritis associated with cartilaginous and ligamentous damage in both wrists. Nineteen months after presentation, intravenous immunoglobulin therapy resulted in clearance of parvovirus B19 viremia and a significant improvement in the symptoms of fatigue and arthritis.

Arthritis, Infectious↗

Parvovirus B19 infection contributes to severe anemia in young children in Papua New Guinea.

BACKGROUND: Severe anemia (hemoglobin level, <50 g/L) is a major cause of death among young children, and it arises from multiple factors, including malaria and iron deficiency. We sought to determine whether infection with parvovirus B19 (B19), which causes the cessation of erythropoiesis for 3-7 days, might precipitate some cases of severe anemia. METHODS: Archival blood samples collected in the Wosera District of Papua New Guinea, from 169 children 6 months-5 years old with severe anemia and from 169 control subjects matched for age, sex, and time were tested for B19 immunoglobulin M (IgM) by enzyme immunoassay and for B19 DNA by nested polymerase chain reaction (PCR). A total of 168 separate samples from children in the Wosera District were tested for B19 IgG. RESULTS: A strong association between acute B19 infection (positive by both IgM and PCR) and severe anemia was found (adjusted odds ratio, 5.61 [95% confidence interval, 1.93-16.3]). The prevalence of parvovirus B19 IgG reached >90% in 6-year-olds. CONCLUSIONS: B19 infections play a significant role in the etiology of severe anemia in this area of malarial endemicity. Given the high levels of morbidity and mortality associated with severe anemia in such regions, the prevention of B19 infection with a vaccine might be a highly effective public health intervention.

Aging↗

cis requirements for the efficient production of recombinant DNA vectors based on autonomous parvoviruses.

The replication of viral genomes and the production of recombinant viral vectors from infectious molecular clones of parvoviruses MVMp and H1 were greatly improved by the introduction of a consensus NS-1 nick site at the junction between the left-hand viral terminus and the plasmid DNA. Progressive deletions of up to 1600 bp in the region encoding the structural genes as well as insertions of foreign DNA in replacement of those sequences did not appreciably affect the replication ability of the recombinant H1 virus genomes. In contrast, the incorporation of these genomes into recombinant particles appeared to depend on in cis-provided structural gene sequences. Indeed, the production of H1 viral vectors by cotransfection of recombinant clones and helper plasmids providing the structural proteins (VPs) in trans, drastically decreased when more than 800 bp was removed from the VP transcription unit. Furthermore, titers of viral vectors, in which most of the VP-coding region was replaced by an equivalent-length sequence consisting of reporter cDNA and stuffer DNA, were reduced more than 50 times in comparison with recombinant vectors in which stuffer DNA was not substituted for the residual VP sequence. In addition, viral vector production was restricted by the overall size of the genome, with a mere 6% increase in DNA length leading to an approximately 10 times lower encapsidation yield. Under conditions fulfilling the above-mentioned requirements for efficient packaging, titers of virus vectors from improved recombinant molecular DNA clones amounted to 5 x 10(7) infectious units per milliliter of crude extract. These titers should allow the assessment of the therapeutic effect of recombinant parvoviruses expressing small transgenes in laboratory animals.

Capsid↗

Adeno-associated virus 2-mediated transduction and erythroid lineage-restricted expression from parvovirus B19p6 promoter in primary human hematopoietic progenitor cells.

Human parvovirus B19 gene expression from the viral p6 promoter (B19p6) is restricted to primary human hematopoietic cells undergoing erythroid differentiation. We have demonstrated that expression from this promoter does not occur in established human erythroid cell lines in the context of a recombinant parvovirus genome (Ponnazhagan et al. J Virol 69:8096-8101, 1995). However, abundant expression from this promoter can be readily detected in primary human bone marrow cells (Wang et al. Proc Natl Acad Sci USA 92:12416-12420, 1995; Ponnazhagan et al. J Gen Virol 77:1111-1122, 1996). In the present studies, we investigated the pattern of expression from the B19p6 promoter in primary human bone marrow-derived CD34+ HPC undergoing differentiation into myeloid and erythroid lineages. CD34+ cells were transduced with recombinant adeno-associated virus 2 (AAV) vectors containing the beta-galactosidase (lacZ) gene under the control of the following promoters/enhancers: the cytomegalovirus promoter (vCMVp-lacZ), B19p6 promoter (vB19p6-lacZ), B19p6 promoter with an upstream erythroid cell-specific enhancer element (HS-2) from the locus control region (LCR) from the human beta-globin gene cluster (vHS2-B19p6-lacZ), and the human beta-globin gene promoter with the HS-2 enhancer (vHS2-beta p-lacZ). Transgene expression was evaluated either 48 h after infection or following erythroid differentiation in vitro for 3 weeks. Whereas high-level expression from the CMV promoter 48 h after infection diminished with time, low-level expression from the B19p6 and the beta-globin promoters increased significantly following erythroid differentiation. Furthermore, in HPC assays, there was no significant difference in the level of expression from the CMV promoter in myeloid or erythroid cell-derived colonies. Expression from the B19p6 and the beta-globin promoters, on the other hand, was restricted to erythroid cell colonies. These data further corroborate that the B19p6 promoter is erythroid cell-specific and suggest that the recombinant AAV-B19 hybrid vectors may prove useful in gene therapy of human hemoglobinopathies in general and sickle cell anemia and beta-thalassemia in particular.

Anemia, Sickle Cell↗

Parvovirus H-1-induced tumor cell death enhances human immune response in vitro via increased phagocytosis, maturation, and cross-presentation by dendritic cells.

Oncotropic and oncolytic viruses have attracted high attention as antitumor agents because they preferentially kill cancer cells in vitro and reduce the incidence of spontaneous, induced, or implanted animal tumors. Some autonomous parvoviruses (H-1, minute virus of mice) and derived recombinant vectors are currently under preclinical evaluation. Still not fully understood, their antitumor properties involve more than just tumor cell killing. Because wild-type parvovirus-mediated tumor cell lysates (TCLs) may trigger antigen-presenting cells (APCs) to augment the host immune repertoire, we analyzed phagocytosis, maturation, and crosspresentation of H-1-induced TCLs by human dendritic cells (DCs). We first established H-1-mediated oncolysis in two HLA-A2(+) and A2(-) variant melanoma cell clones. Monocyte-derived immature DCs phagocytosed H- 1-infected TCLs as well as ultraviolet-induced apoptotic TCLs and better than freeze-thaw-induced necrotic TCLs. Immature DCs incubated with H-1-induced TCLs acquired specific maturation markers comparable to a standard cytokine cocktail. Furthermore, A2(+) DCs pulsed with H-1-infected A2(-) TCLs cross-presented melanoma antigens to specific cytotoxic T lymphocytes (CTLs) and released proinflammatory cytokines. This shows for the first time that tumor cell killing by a wild-type oncolytic virus directly stimulates human APCs and CTLs. Because H-1-infected tumors enhance the immune repertoire, the clinical perspectives of parvoviral vectors are even more promising.

Animals↗

Chronic parvovirus infection in a presumably immunologically healthy woman.

Infection due to parvovirus B19 is common and usually resolves over several weeks. Prolonged infection has been reported primarily in immunodeficient hosts. The present report describes a chronic infection in an apparently immunologically healthy woman. The illness was characterized by recurrent episodes of paresthesia without anemia. Laboratory studies demonstrated persistence of parvovirus-specific DNA for nearly 4 years.

Antibodies, Viral↗

Prenatal diagnosis of intrauterine infection with parvovirus B19 by the polymerase chain reaction technique.

Human parvovirus B19 is a recently recognized cause of fetal hydrops and death. Efforts to characterize the natural history of fetal infection with this virus have been hampered by the lack of sensitive and specific tests for diagnosis in utero. Using the highly sensitive polymerase chain reaction (PCR) assay, we determined the fetal infection status in 56 pregnancies by testing amniotic fluid, fetal serum, and maternal serum for B19 DNA and antibodies. Factors associated with a high risk of B19 infection were fetal disease, exposure to persons with erythema infectiosum, or signs or symptoms of acute B19 infection. Fifteen women (27%) were B19 IgM-positive, a status suggesting recent infection; the positivity of all of the corresponding fetal specimens for B19 DNA in the PCR was indicative of fetal infection. In four of these cases, serial ultrasonographic examinations documented spontaneous resolution of fetal hydrops. Twenty-four women (43%) were IgG-positive and IgM-negative; this pattern suggested prior infection. The PCR gave positive results, consistent with recent maternal infection, in four of these cases. Seventeen women (30%) were IgG-negative and IgM-negative, a pattern suggesting no prior infection; the PCR results in four cases were indicative of a possible early maternal infection or a possible atypical immune response. The PCR is a sensitive and rapid method for the diagnosis of intrauterine infection with human parvovirus B19 and promises to facilitate studies of the natural history and treatment of this infection.

Adolescent↗

Spectrum of parvovirus B19 infection: analysis of an outbreak of 43 cases in Cadiz, Spain.

In the spring of 1993, an epidemic of infection with human parvovirus B19 occurred in Cadiz, Spain. Evaluation of the 43 patients in whom this diagnosis was confirmed revealed four groups of predominant manifestations: (1) hematologic manifestations in six cases (13.9%), including four of aplastic crisis and two of pancytopenia; (2) dermatologic manifestations in 23 cases (53.4%), including 10 of erythema infectiosum and one of erythema multiforme ampullosum; (3) arthralgias/arthritis in nine cases (20.9%), including two with a chronic course; and (4) infection during pregnancy in three cases (7.0%), including two that ended in abortion. Of the 43 patients, 37.2% presented with fever and adenopathies, and these were the only manifestations in two cases. The appearance of clinical disease correlated with modifications in isotype and serum level of specific antibodies to parvovirus B19; the disappearance of IgM antibodies coincided with the resolution of clinical manifestations. Although their presence did not correlate with the course of the disease, the detection of circulating immune complexes in 81.6% of cases supports the possibility that some manifestations were immune mediated.

Adolescent↗

Antibodies to the nonstructural protein of parvovirus B19 in persistently infected patients: implications for pathogenesis.

Three patients with persistent parvovirus B19 infection, as documented by the prolonged presence of IgM directed to the viral capsid proteins and detection of viral DNA in serum by dot-blot hybridization or polymerase chain reaction (PCR), were investigated for the presence of antibodies to the nonstructural protein NS-1 of parvovirus B19. This was done by using an ELISA based on recombinant NS-1 protein. Whereas control sera displayed no reactivity, sera from persistently infected patients showed a strong specific antibody response to NS-1. Patients were followed for 3-18 months, during which IgM titers declined but IgG directed to the nonstructural protein remained detectable. The appearance of NS-1-specific antibodies might indicate an altered course of viral infection leading to the establishment of persistently active infection and subsequent destruction of cells of nonerythroid lineage.

Adult↗

Epitope type-specific IgG responses to capsid proteins VP1 and VP2 of human parvovirus B19.

Temporal reactivities of IgG towards native and linear antigenic determinants in assembled capsids or isolated structural proteins of human parvovirus B19 were measured by an epitope type-specific IgG EIA and by immunoblots. Antigens used were baculovirus-expressed B19 capsids composed of the proteins VP1 and VP2 in their native proportion, VP2 alone, or a prokaryotic VP1 fusion protein. Follow-up sera after primary infection were compared with samples from previously infected persons. The IgG responses during acute and early convalescence phases were directed towards both conformational and linear epitopes of VP2. The antibodies against the linear VP2 epitopes disappeared abruptly within 6 months; however, the conformational VP2 antibodies persisted. The epitope type-specific IgG reactivity of VP1 was strikingly different from that of VP2. On the basis of these results, two novel tests were developed for patient diagnosis. Both tests are suitable for verifying the time of human parvovirus infection.

Antibodies, Viral↗

A study of the role of parvovirus B19 in rheumatoid arthritis.

Serum and synovial tissue from 26 patients with rheumatoid arthritis (RA) (according to the diagnostic criteria of the American Rheumatism Association) and 26 patients with osteoarthritis (OA) were examined. Among the RA group, the female to male ratio was 4.2:1, and the age range was 44-82 yr with a mean of 64.0 yr; joints from which synovium was sampled were hip (n = 12), knee (n = 9), ankle (n = 3) and shoulder (n = 2). The duration of rheumatoid disease ranged from 6 to 24 yr with a mean of 13.9 yr. Among the OA group, the female to male ratio was 2.25:1, and the age range was 51-88 yr with a mean of 68.2 yr; joints from which synovium was sampled were hip (n = 18) and knee (n = 8). Twenty-one patients from the RA group and 20 patients from the OA group had evidence of previous parvovirus B19 infection (serum anti-B19 IgG), and all patients from both groups were serum anti-B19 IgM negative. Synovial sections from all 52 patients were stained with mouse monoclonal antibodies, 3H8 (to B19 capsid proteins) and alpha-P (to blood group P antigen). All tissue sections examined were found to be negative for both B19 capsid proteins and blood group P antigen. Using a nested polymerase chain reaction (PCR) assay, all patients were negative for serum B19 DNA. However, B19 DNA was demonstrated in the synovium of 10 of 26 RA patients and 9 of 26 OA patients; uncorrected chi 2 value = 0.08; degrees of freedom = 1; P = 0.77. All 19 patients testing positive for synovial B19 DNA had evidence of prior exposure to B19 infection (serum anti-B19 IgG). In conclusion, although there is published evidence of chronic rheumatoid-like arthropathy following acute parvovirus B19 infection, our findings do not support the involvement of B19 in the aetiopathogenesis of RA.

Adult↗

Antibodies to parvovirus B19 non-structural protein are associated with chronic but not acute arthritis following B19 infection.

OBJECTIVE: To determine the incidence and significance of antibodies to the parvovirus B19 non-structural (NS1) protein in B19-infected persons during acute infection and convalescence. METHODS: The B19 NS1 protein was expressed in SF9 cells using the baculovirus expression system and was used to prepare immunofluorescence slides. These were used in a fluorescent antibody test to determine anti-B19 NS1 IgG in a well-characterized cohort of 53 persons at the time of acute B19 infection and again after a follow-up period of 26-85 months. Results were examined for statistical significance by the use of Fisher's exact test. RESULTS: NS1 antibodies were detected in five of 32 persons with acute B19 infection (four with arthritis) and 10 of 53 persons with past B19 infection (six with chronic arthritis and two with chronic arthritis and chronic fatigue syndrome). Regarding the correlation of NS1 antibodies and arthritis, at the time of acute infection four of 24 persons with arthritis had NS1 antibodies detected compared with one of eight persons with any other symptoms (P: = 1). During convalescence, eight of 20 persons with chronic arthritis had NS1 antibodies compared with two of 33 with symptoms of any other category (all except one were asymptomatic) (P: = 0.007). All 10 patients with NS1 antibodies during convalescence had arthritis during acute infection, which persisted in eight persons until the time of follow-up. CONCLUSION: Antibodies to parvovirus B19 NS1 protein are associated with chronic but not with acute arthritis after B19 infection.

Acute Disease↗