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J. Virol. doi:10.1128/JVI.01692-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Evolution to Pathogenicity of the Parvovirus MVM in Immunodeficient Mice Involves Genetic Heterogeneity at the Capsid Domain Determining Tropism

Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), 28049 Cantoblanco, Madrid, Spain; Yale University School of Medicine, Cedar Street 333, CT, USA; 3M Pharmaceuticals 3M Center, Building 270-3S-05 St. Paul, MN 55144-1000, Ciemat, Avda. Complutense 22, 28040 Madrid, Spain

^* To whom correspondence should be addressed. Email: jmalmendral{at}cbm.uam.es.

	Abstract

Very little is known about the role that evolutionary dynamics plays in diseases caused by mammalian DNA viruses. To address this issue in a natural host model, the pathogenesis and genetics of the attenuated fibrotropic (p) and the virulent lymphohematotropic (i) strains of the parvovirus minute virus of mice (MVM), and of two invasive MVMp variants carrying the I362S or K368R changes in the VP2 major capsid protein, were compared in the infection of severe combined immunodeficient (SCID) mice. In oronasal inoculations, the I362S and K368R viruses caused lethal leukopenia by 14-18 weeks post-infection (wpi), characterized by tissue damage and inclusion bodies in hemopoietic organs, a pattern of disease found by 7 wpi in infections with the MVMi strain. The MVMp populations emerging in leukopenic mice showed consensus sequence changes to the MVMi genotype at VP2 G321E and A551V residues in the I362S virus infections, or at A551V and V575A in the K368R virus infections, and a high genetic heterogeneity within a capsid domain at the two-fold depression where these residues lay. Amino acids conforming this capsid domain are important MVM tropism determinants, as exemplified by the switch in MVMi host range toward mouse fibroblasts conferred by coordinated changes of some of them, as well as by the essential character of glutamate at residue 321 for maintaining MVMi tropism toward primary hemopoietic precursors. The few viruses within the mutant spectrum in mice that maintained the respective parental 321G and 575V residues were infectious in plaque assay, whereas the main consensus genotypes exhibited low fitness in culture. Consistent with this, a recombinant MVMp virus carrying the consensus mutations arising in mice in the K368R background failed to initiate infection in cell lines of different tissue origins, even though it caused lethal leukopenia of rapid course in SCID mice. This parental consensus genotype prevailed during leukopenia development, but plaquing viruses emerged in affected organs with the 575A residue reverted to valine. The disease caused by this DNA virus in mice, therefore, involves the generation of heterogeneous viral populations, that may cooperatively interact for the hemopoietic syndrome. The evolutionary changes delineate a sector of the surface of the capsid determining tropism, which surrounds the sialic acid-receptor binding domain.