Abstract
Productive infection of human parvovirus B19 (B19V) exhibits high tropism for burst forming unit erythroid (BFU-E) and colony forming unit erythroid (CFU-E) progenitor cells in human bone marrow and fetal liver. This exclusive restriction of the virus replication to human erythroid progenitor cells is partly due to the intracellular factors that are essential for viral DNA replication, including erythropoietin signaling. Efficient B19V replication also requires hypoxic conditions, which upregulate the signal transducer and activator of transcription 5 (STAT5) pathway, and phosphorylated STAT5 is essential for virus replication. In this study, our results revealed direct involvement of STAT5 in B19V DNA replication. Consensus STAT5-binding elements were identified adjacent to the NS1-binding element within the minimal origins of viral DNA replication in the B19V genome. Phosphorylated STAT5 specifically interacted with viral DNA replication origins both in vivo and in vitro, and was actively recruited within the viral DNA replication centers. Notably, STAT5 interacted with minichromosome maintenance (MCM) complex, suggesting that STAT5 directly facilitates viral DNA replication by recruiting the helicase complex of the cellular DNA replication machinery to viral DNA replication centers. The FDA-approved drug pimozide dephosphorylates STAT5, and it inhibited B19V replication in ex vivo expanded human erythroid progenitors. Our results demonstrated that pimozide could be a promising antiviral drug for treatment of B19V-related diseases.
Highlights
Human parvovirus B19 (B19V) is a small, non-enveloped parvovirus with a single-stranded DNA genome of 5.6 kb
Our results previously demonstrated that pSTAT5A has a critical role in B19V infection of human erythroid progenitor cells (EPCs) cultured under hypoxic conditions [25], leading us to consider in this study whether specific inhibition of signal transducer and activator of transcription 5 (STAT5) phosphorylation affects B19V replication
These results suggested that inhibition of STAT5 phosphorylation abolishes viral DNA replication in B19V-infected CD36+ EPCs
Summary
Human parvovirus B19 (B19V) is a small, non-enveloped parvovirus with a single-stranded (ss) DNA genome of 5.6 kb. It belongs to the genus Erythroparvovirus of the Parvoviridae family [1]. B19V infects human erythroid progenitor cells (EPCs) through initial attachment to its primary receptor (P-antigen) [8] and interaction with co-receptors, resulting in virus internalization [9,10]. Virus replication and assembly take place in the nuclei of infected cells. The B19V double-stranded (ds) DNA replicative form (RF) genome expresses the large non-structural NS1 protein, two small non-structural proteins (the 11-kDa and 7.5-kDa proteins), and two capsid proteins (VP1 and VP2) [11,12,13]
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