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Journal of Virology, August 2003, p. 8495-8503, Vol. 77, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.15.8495-8503.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Parvovirus Infection Suppresses Long-Term Repopulating Hematopoietic Stem Cells

José C. Segovia,1 Guillermo Guenechea,1 Jesús M. Gallego,2,{dagger} José M. Almendral,2* and Juan A. Bueren1

Hematopoietic Gene Therapy Project, CIEMAT/Fund. M. Botín, 28040 Madrid,1 Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), 28049 Cantoblanco, Madrid, Spain2

Received 29 January 2003/ Accepted 14 May 2003

The functional disturbance of self-renewing and multipotent hematopoietic stem cells (HSCs) in viral diseases is poorly understood. In this report, we have assessed the susceptibility of mouse HSCs to strain i of the autonomous parvovirus minute virus of mice (MVMi) in vitro and during persistent infection of an immunodeficient host. Purified 5FUr Lin- Sca-1+ primitive hematopoietic precursors were permissive for MVMi genome replication and the expression of viral gene products. The lymphoid and myeloid repopulating capacity of bone marrow (BM) cells was significantly impaired after in vitro infection, although the degree of functional effect proportionally decreased with the posttransplantation time. This indicated that MVMi targets the heterogeneous compartment of repopulating cells with differential affinity and suggests that the virus may persist in some primitive HSCs in the quiescent stage, killing those eventually recruited for proliferative activity. Immunodeficient SCID mice oronasally infected with MVMi were cured of the characteristic virus-induced lethal leukopenia by transplantation of immunocompetent BM grafts. However, two double-stranded viral DNA species, probably uncommon replicative intermediates, remained in the marrow of every transplanted mouse months after infectious virus clearance. Genetic analysis of the rescued mice showed that the infection ensured a stable engraftment of donor hematopoiesis by markedly depleting the pool of endogenous HSCs. The MVMi-induced suppression of HSC functions illustrates the accessibility of this compartment to infection during a natural viral hematological disease. These results may provide clues to understanding delayed hematopoietic syndromes associated with persistent viral infections and to prospective gene delivery to HSCs in vivo.

* Corresponding author. Mailing address: Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Universidad Autónoma de Madrid, 28049 Cantoblanco, Madrid, Spain. Phone: 34-913978048. Fax: 34-913978087. E-mail: jmalmendral{at}cbm.uam.es.

{dagger} Present address: Clínica Reyes Católicos, 09005 Burgos, Spain.

Journal of Virology, August 2003, p. 8495-8503, Vol. 77, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.15.8495-8503.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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