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Advances in Human B19 Erythrovirus Biology

Annabelle Servant-Delmas, Jean-Jacques Lefrère, Frédéric Morinet, Sylvie Pillet
DOI: 10.1128/JVI.00684-10

ABSTRACT

Since its discovery, human parvovirus B19 (B19V), now termed erythrovirus, has been associated with many clinical situations (neurological and myocardium infections, persistent B19V DNAemia) in addition to the prototype clinical manifestations, i.e., erythema infectiosum and erythroblastopenia crisis. In 2002, the use of new molecular tools led to the characterization of three different genotypes of human B19 erythrovirus. Although the genomic organization is conserved, the geographic distribution of the different genotypes varies worldwide, and the nucleotidic divergences can impact the molecular diagnosis of B19 virus infection. The cell cycle of the virus remains partially unresolved; however, recent studies have shed light on the mechanism of cell entry and the interactions of B19V proteins with apoptosis pathways.

Before the recent descriptions of human bocavirus (2) and human parvovirus 4 (PARV4) (41), parvovirus B19 ([B19V] or erythrovirus B19) was the only known member of the Parvoviridae family to infect humans. The Erythrovirus genus contains B19V, erythroviruses that infect several simian species, and the parvovirus from Manchurian chipmunks (87a). These viruses share the remarkable property of replicating in and destroying erythroid progenitors. This strong in vitro tropism explains the difficulties in studying the replicative cycle of these viruses; indeed, the in vitro production and culture of erythroid progenitor cells remain delicate. An infectious B19V clone was described only recently (102), and its use, although mostly limited and allowing only a small amount of progeny production, led to constructions of recombinant viruses that were helpful in understanding the steps of the virus life cycle and the toxicity of the virus.

CLINICAL MANIFESTATIONS

Discovered in 1975 (19), B19V can cause a wide range of mild and self-limiting clinical manifestations, such as erythema infectiosum (fifth disease) and oligoarthritis (98). B19V infection can also cause acute anemia by aplastic crisis in patients whose red blood cells have shortened survival times (i.e., patients with sickle cell disease, thalassemia, spherocytosis, or any disorder of hemoglobin gene expression or red cell membrane constitution), chronic anemia in patients with congenital immunodeficiencies or human immunodeficiency virus (HIV) infection or who are undergoing chemotherapy for malignancies or organ transplants (48, 58), and hydrops fetalis or intrauterine death in infected fetuses (86). Recently, cases of neurological manifestations have been associated with B19V infection (22), as have myocardium infections (4, 5, 47, 83), and the spectrum of B19V-linked diseases may further increase.

The primary route of transmission of B19V is the respiratory tract (via aerosol droplets), with a majority of infections occurring during childhood, but the infection may also be transmitted by organ transplantation and especially by transfusion of blood components, in particular by packed red cells from blood collected during the short preseroconversion viremic phase (17, 42, 101).

PERSISTENT INFECTIONS

The natural course of an acute B19V infection is classically controlled by neutralizing antibodies in immunologically competent individuals. A transient, high-level viremia is present for less than 1 week and then declines with the appearance of specific IgM antibodies that persist for 8 to 10 weeks (3) and specific IgG antibodies that persist for the lifetime of the individual. Persistent infections may be observed in immunocompromised patients unable to produce neutralizing antibodies and to clear the virus, leading to chronic carriage of B19V with or without anemia (28, 29, 49). However, even though the immune response is able to clear infection in healthy individuals and to provide lifelong protection against B19V, persistence of infection in the bone marrow has been reported in immunocompetent individuals with or without symptoms (12, 57, 71), and recently, persisting low levels of B19V DNA has been evidenced in the blood of immunocompetent individuals several years after primary infection (13, 50). The mechanism of such chronic carriage of B19V is unclear.

EPIDEMIOLOGY AND GENETIC DIVERSITY

B19V infection is a common infection. Its seroprevalence increases with age, from 2 to 10% in children under 5 years old, to 40 to 60% in adults more than 20 years old, and up to 85% in the elderly population. Infections are more common in late winter and early summer, with epidemic peaks every 3 to 4 years (7).

Genetic diversity among B19V isolates was reported to be very low, with a single prototype, B19V (54), until 2002, when new sequence analysis of human erythroviruses showed organization into three genotypes. Genotype 1 includes B19V and two new genotypes with a genetic diversity markedly distinct (>9% nucleotide divergence on the whole genome) from that of B19V (Fig. 1) (85). Genotype 2 includes the Lali strain (38) and the A6 strain (70), genotype 3a the V9 strain (69), and genotype 3b the D91.1 strain (85).

FIG. 1.
FIG. 1.

Phylogenetic relationships among human erythroviruses on NS1-VP1u sequences (858 bp). (Adapted from reference 85.) Sequence analysis was performed by using the neighbor-joining algorithm based on the Kimura 2 parameter distance estimation method. Strain sequences are distributed into three clusters: genotype 1 (prototype, pvbaua; GenBank accession number M13178), genotype 2 (prototype, Lali; GenBank accession number AY044266), genotype 3a (prototype, V9; GenBank accession number AX003421), and genotype 3b (prototype, D91.1; GenBank accession number AY083234).

The prevalence of each genotype varies with geographic origin, population, and sample type. For example, in tissue biopsy specimens, the prevalences of the different genotypes range from 28% (47) to 81% for genotype 1 (96), from 8% (84) to 71% for genotype 2 (47), and from 0% to 50% (47, 72) for genotype 3 (84). A study based on the detection of B19V DNA in tissues suggested that genotypes 1 and 2 circulated in Northern Europe with equal frequencies more than half a century ago and that after this period, genotype 2 viruses disappeared. Genotype 2 viruses were strictly confined to subjects born before 1973, and genotype 3 has never attained wide occurrence in this area during the past 70 years (72). In pools of Finnish plasma, only genotype 1 viruses were detected (37), while 100% of detected strains in blood donors in Ghana were from genotype 3 (11). A recent study based on phylogenetic analysis of human erythrovirus sequences from 11 countries in Europe, Asia, and West Affrica confirmed the worldwide predominance of genotype 1 and suggested the spread of genotype 3b: (39). 91.5% of patients with fever or rash were infected by a genotype 1 erythrovirus and only 8.5% by a genotype 3 virus. The latter genotype seems to be predominant in some parts of West Africa and was also isolated in three non-African countries. The high level of genetic diversity of genotype 3 viruses, of which there are several clusters within subtypes 3a and 3b, compared to that of genotype 1 and 2 viruses is indicative of a longer evolutionary history, probably in Africa (39). Regarding pathogenic properties, the clinical spectrum associated with genotype 2 or 3 virus infection has been found to be similar to that observed with genotype 1 infection.

B19V ENTRY INTO CELLS

Like all members of the Parvoviridae family, B19V is a small, nonenveloped virus (around 20 nm in diameter) (Fig. 2). X-ray crystallography has been used to determine the icosahedral structure of the viral capsid and the organization of capsid protein domains (1, 16, 44). The B19V core is constituted of 60 molecules of capsid proteins (viral protein [VP]). VP2 (58 kDa) is the major protein (95% of the capsid composition) and contains receptor- and coreceptor-binding domains as well as self-assembly domains that lead to the formation of highly stable particles. Its structure is formed by an eight-stranded β-barrel connected by variable loops. VP2 corresponds to the C-terminal region of VP1, and the first 227 amino acids of VP1 constitute the VP1 unique (VP1u) region. VP1 (81 kDa) is not necessary for capsid formation, but the VP1u region contains elements that are critical for virus entry, especially an original phospholipase A2 (PLA2) domain (100).

FIG. 2.
FIG. 2.

B19V particles isolated from serum and observed by immune electron microscopy.

The main receptor of B19V is the P antigen, or globoside (8, 9). The α5β1 integrin complex is clearly implicated as a coreceptor for the entry of B19V into permissive cells, i.e., erythroid progenitor cells (94). The Ku80 DNA-binding protein has also been implicated in B19V cell entry (67). Investigation of the entry steps of B19V is difficult because of its strong tropism for primary erythroid progenitors in vitro. However, the entry routes of different animal parvoviruses (especially canine parvovirus, minute virus of mice, and porcine parvovirus) have been described and could serve as good models for that of B19V (20, 35, 90). After fixation to the receptor/coreceptor complex, the animal parvoviruses enter into the cytoplasm by endocytosis, implying the clathrin and dynamin proteins and a cytoskeleton network. The transit from early to late endosomes brings the endocytic vesicles to the nuclear periphery. The low pH of the endocytic vesicles leads to conformational modifications that allow exposure of the VP1u region, specifically the PLA2 domain and nuclear localization signal(s) (NLS), at the surface of the capsid. The PLA2 domain of parvoviruses contains a catalytic site and a Ca-binding domain necessary for enzymatic activity (100). The PLA2 domains of the different parvoviruses constitute the XIII group of the PLA2 superfamily (10). The parvoviral PLA2 domain cleaves the vesicle membrane, liberating the viral particle near the nuclear membrane. NLSs allow the binding of capsid proteins to cellular importin(s) and the translocation of the viral genome into the nucleus, probably through the nuclear-pore complex (90).

This model of cell entry can also be applied to B19V infection. Rap1, a small GTPase of the Ras superfamily, plays a role in the cytoplasmic trafficking of B19V by regulating the β1 integrin coreceptor and/or modulating the microtubule network during the trafficking of viral particles in the cytoplasm (95). B19V particles have been clearly observed by electron microscopy in endocytic vesicles from infected erythroid cells, suggesting that endocytosis is the mechanism of B19V cell entry (92). The PLA2 domain is localized between amino acids 130 to 195 in VP1u of B19V (21) and is conserved among different genotypes. This domain is critical for B19V entry; virions with mutations in the VP1u region are not able to enter into the nucleus of the infected cell (27). No NLS implicated in nuclear entry has been described so far for B19V; a NLS has been localized to the C-terminal region of VP2, but its role in the entry of B19V has not been studied (78).

VIRUS REPLICATION AND CELL APOPTOSIS

The B19V genome is a single-stranded DNA molecule; the positive or negative strand is randomly encapsidated into viral capsids. The unique functional promoter P6 (located at map unit 6) controls the synthesis of at least nine transcripts that encode one nonstructural protein (NS1), two structural capsid proteins (VP1 and VP2), and two small proteins of 7.5 and 11 kDa (Fig. 3A and B) (15, 32, 74). NS1 acts as a strong transcription activator by recruiting numerous cellular transcription factors (62, 81, 89) and participates in viral replication through the properties of its helicase and endonuclease. A blockage of the production of full-length transcripts at the internal polyadenylation site is associated with the limited permissiveness of B19V infection (52) because it limits viral expression of the VP proteins. This blockage can take place at the translation step (31, 76), and it has recently been demonstrated that it can be overcome by viral genome replication, leading to the production of all viral proteins in permissive cells (32). At a high multiplicity of infection, B19V DNA within the nuclei of infected erythroid cells peaks at 48 h, whereas it appears in culture supernatants at 32 h (75). Viral replication is enhanced by environmental factors such as a decrease in oxygen concentration in cell culture (79), by expression of adenovirus transactivators (33), and by chloroquine and its derivatives (6). Recently, in vitro production of purified CD36+ primary erythroid progenitors permitted us and others to routinely replicate B19V (26, 79, 87, 97).

FIG. 3.
FIG. 3.

Locations and synthesis of viral mRNAs. (A) Transcription map of B19V genes (15, 32, 74). The 9 main transcripts are represented. (B) Expression of viral mRNAs in primary erythroid cells. The viral mRNAs were detected by Northern blotting, using a radiolabeled probe in noninfected and infected primary erythroid cells as described previously (79).

In 1983, Mortimer and colleagues suggested that B19V was cytotoxic for erythroid progenitors (65). The link between toxicity and apoptosis was first suggested by ultrastructural examination of B19V-infected fetal erythroid progenitors (63, 64) and then in an erythroid cell line transfected with the NS1 gene, where activation of caspase 3 was demonstrated (61). The nucleoside triphosphate-binding domain of the NS1 protein of B19V was considered to be involved in B19V-mediated apoptosis in erythroid and nonerythroid cells (61, 62, 80). Induction of erythroid cell apoptosis by B19V also involves the interaction of NS1 protein with the tumor necrosis factor (TNF) receptor-signaling pathway (87), leading to the activation of caspases 3 and 6. The proapoptotic activity of the B19V NS1 protein is shared by the NS1 proteins of the 3 genotypes of B19V (15) and those of other parvoviruses (18, 66, 73, 82).

Two small proteins of 7.5 and 11 kDa are encoded by the abundant small mRNA and are expressed in infected erythroid progenitor cells (Fig. 3B). Their functions have been poorly explored, but as they are expressed by a small genome with limited coding capacities, they should play a critical role in the B19V cell cycle or pathogenesis. The 11-kDa protein contains several proline-rich motifs, which share homologies with the Src homology 3 (SH3)-binding domain of eukaryotic proteins, and binds to the growth factor receptor-binding 2 (24), suggesting that it interacts with the cytoplasmic region of some growth factor receptors, leading to perturbation of signal transduction. Blocking the expression of the 11-kDa protein in recombinant virions significantly reduces viral infectivity; the expression of the small protein could be critical for VP2 protein expression and trafficking in infected cells (102). Chen and colleagues showed recently that the 11-kDa protein was highly expressed (at least 100 times more than NS1) in erythroid progenitors, mostly in the cytoplasm, and was a major inducer of apoptosis by the activation of caspase 10 (an initiator caspase recruited at the top of the caspase signaling cascade in the death receptor signaling pathway) (14).

Moreover, B19V DNA could activate Toll-like receptor 9 into erythroid cells, leading to inhibition of cell growth (34). Parvovirus DNA hairpins formed by the inverted terminal repeats (43, 88), as well as B19V capsid proteins (51, 64, 99), have also been suspected of toxicity for infected cells. B19V-induced erythroblastopenia could then be multifactorial.

IMMUNOLOGICAL DYSFUNCTIONS

Immunopathological phenomena during or following B19V infections have been described, and B19V infection may even trigger or aggravate autoimmune diseases (55, 91). Polyclonal stimulation of the immune system by B19V, with the production of various autoantibodies, including antinuclear antibodies, has been effectively observed during B19V infections (36, 68). Molecular mimicry of viral epitopes by cellular autoantigens and the production of anti-idiotype antibodies could participate in the production of self-antibodies and in autoimmune reactions (53, 55, 56). High levels of proinflammatory cytokines are observed during B19V infection, especially those of interleukin-1β (IL-1β), Il-6, gamma interferon, and TNF alpha (TNF-α) (45, 93). Il-6 and TNF-α production can be stimulated by the viral transactivator NS1 (30, 59, 60). Genetic variability in the cytokine response has been associated with the likelihood of developing symptoms during B19V infection (46). A remarkably prolonged activation of virus-specific CD8+ T cells has been observed after acute B19V infection (40). Recently, productive B19V infection of endothelial cells has been obtained in vitro (77), and the stimulation and/or persistent infection of such cells could play a role in the pathogenesis of the virus (23).

CONCLUSION

Despite recent new discoveries concerning viral entry and genetic diversity, there is still a lack of sufficient data for a fully comprehensive understanding of B19V infection. The principal reason for the lack of data is the difficulty of propagating this virus in vitro. Only primary erythroid progenitors are permissive to B19V, and they are not routinely available. This selective tropism for the erythroid-cell lineage has not yet been explained.

There is no antiviral agent with which to treat B19V infections. The administration of gamma globulin helps to control chronic infections, and transfusions of red blood cells control acute anemia. No vaccine is yet available, and the target population that would benefit from a vaccine remains unclear.

ACKNOWLEDGMENTS

We are indebted to Marianne Leruez for correcting English language usage and to Jean Rommelaere for critically reading the manuscript and for constant interest in our work.

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Author Bios

Embedded Image Annabelle Servant-Delmas (Ph.D.) is a researcher at the National Institute of Blood Transfusion, Paris, France. Since 1997, her research has concerned blood-transmissible infectious agents, particularly human parvovirus B19.

Embedded Image Jean-Jacques Lefrère is Professor of Hematology in the Department of Blood Transmissible Agents, National Institute of Blood Transfusion, Paris, France. Since 1985, his research has concerned blood-borne agents and transfusion safety.

Embedded Image Frédéric Morinet is Professor of Virology at University Paris Diderot—Paris VII and a medical doctor at the Saint-Louis Hospital. Since 1984, his research has concerned human parvovirus B19.

Embedded Image Sylvie Pillet (Pharm.D., Ph.D.) is a biologist in the Laboratory of Virology of University Hospital in Saint-Etienne, France. Since she earned her doctorate degree working on human parvovirus B19, her research has concerned enterovirus genotyping and the role of cytomegalovirus in inflammatory bowel diseases.

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KEYWORDS

Parvoviridae Infections
Parvovirus B19, Human

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