Advances in the Development of Antiviral Strategies against Parvovirus B19

Abstract

Parvovirus B19 (B19V) is a human pathogenic virus, responsible for an ample range of clinical manifestations. Infections are usually mild, self-limiting, and controlled by the development of a specific immune response, but in many cases clinical situations can be more complex and require therapy. Presently available treatments are only supportive, symptomatic, or unspecific, such as administration of intravenous immunoglobulins, and often of limited efficacy. The development of antiviral strategies against B19V should be considered of highest relevance for increasing the available options for more specific and effective therapeutic treatments. This field of research has been explored in recent years, registering some achievements as well as interesting future perspectives. In addition to immunoglobulins, some compounds have been shown to possess inhibitory activity against B19V. Hydroxyurea is an antiproliferative drug used in the treatment of sickle-cell disease that also possesses inhibitory activity against B19V. The nucleotide analogues Cidofovir and its lipid conjugate Brincidofovir are broad-range antivirals mostly active against dsDNA viruses, which showed an antiviral activity also against B19V. Newly synthesized coumarin derivatives offer possibilities for the development of molecules with antiviral activity. Identification of some flavonoid molecules, with direct inhibitory activity against the viral non-structural (NS) protein, indicates a possible line of development for direct antiviral agents. Continuing research in the field, leading to better knowledge of the viral lifecycle and a precise understanding of virus-cell interactions, will offer novel opportunities for developing more efficient, targeted antiviral agents, which can be translated into available therapeutic options.

Keywords: Parvovirus B19; antiviral compounds; brincidofovir; cidofovir; coumarin derivatives; erythroid progenitor cells; flavonoids; hydroxyurea; intravenous immunoglobulin (IVIG).

Figure 1

B19V genome organization. Top: major open reading frames identified in the positive strand of genome; arrows indicate the coding sequences for the viral proteins. NS, non-structural protein; VP, structural proteins, colinear VP1 and VP2, assembled in a T = 1 icosahedral capsid; and 7.5 kDa, 9.0 kDa, and 11 kDa: minor non-structural proteins. Center: a schematic diagram of B19V genome indicating the two inverted terminal regions (ITR), and the internal region (IR) with the distribution of cis-acting functional sites (P6, promoter; pAp1, pAp2, proximal cleavage-polyadenylation sites; pAd, distal cleavage-polyadenylation site; D1 and D2, splice donor sites; A1.1, A1.2, A2.1, and A2.2, splice acceptor sites). Bottom: simplified transcription map of B19V genome, indicating the five classes of mRNAs (mRNA 1–5) with respective alternative splicing/cleavage forms (dashed), and their coding potential. Adapted from Reference [5].

Figure 2

Outline of B19V replicative cycle in erythroid progenitor cells. 1: virion binding to globoside. 2: extrusion of VP1 unique (VP1u) region and binding to an erythroid specific receptor. 3: clathrin-mediated endocytosis. 4: virions in endosomal vesicles. 5: virion processing within endosomes. 6: VP1u-associated viral phospholipase (vPLA2) mediated virion escape from endosomes. 7: partial uncoating and externalization of viral ssDNA. 8: translocation in the nucleus and complete uncoating. 9: parental ssDNA and onset of macromolecular syntheses. 10: hairpin-primed second strand synthesis. 11: formation of dsDNA replicative intermediate. 12: early phase of transcription on the parental template, mainly of mRNAs for NS protein. 13: dsDNA nicked by NS and priming of replication in coordination with cellular proteins. 14: replication by a rolling hairpin mechanism, via self-primed single-strand displacement mechanisms. 15: late phase of transcription on the replicative intermediates, mainly of mRNAs for VP and 11kDa proteins. 16: progeny ssDNA released from the replicative intermediates. 17: incapsidation of progeny ssDNA molecules in newly formed virions. 18: accumulation of virions before their release via cell lysis or apoptosis. 19: Epo binding by Epo receptor (EpoR), EpoR activation, and STAT5 phosphorilation. 20: pSTAT translocation in the nucleus where it is essential for formation of a functional replicative complex.