A presumed mouse parvovirus with overlooked high toxicity for human primitive CD34 ⁺ hematopoietic precursors <i>in vitro</i> and in bone marrow-humanized mice

Two strains of the minute virus of mice (MVM) parvovirus (of the species <i>Protoparvovirus rodent1</i>), named i (immunosuppressive) and p (prototype), show disparate tropism and pathogenicity in mice. Unlike the virulent MVMi, the MVMp is attenuated and infection-restricted in primary mouse hematopoietic cells; however, it does infect human transformed, established, and stem cells. We thus seek here a putative MVMp natural tropism to humans compared to MVMi. Infectious purified MVMp virions suppress <i>in vitro</i> the clonogenic potential of human committed (erythroid and myeloid) and primitive CD34⁺ progenitors, regardless of the cell source (umbilical cord blood, G-CSF mobilized peripheral blood, or bone marrow), in a multiplicity of infection-dependent manner. Furthermore, primitive CD34⁺ progenitors in culture are permissive to the MVMp cytotoxic NS-1 protein expression and the synthesis of viral genome replicative intermediates. None of these features is shared by MVMi. In consistency, MVMp suppresses the pool of CD34+ progenitors in bone-marrow-humanized immunodeficient NSG mice and severely compromises their survival, whereas in basal NSG mice, it replicates to several thousand-fold lower levels than MVMi and undergoes evolution to variants carrying genetic changes at the capsid tropism determinant binding sialic acid types. We suggest that MVMp may have originated from a MVMi-like mouse parvovirus upon adaptation to human sialic acid receptors in immunocompromised individuals. Extensive serological and genetic screens failed to demonstrate circulating MVMp in Eurasian and African human populations, including hematopoietic patients. Nevertheless, the high MVMp cytotoxicity to human primitive hematopoietic progenitors and rapid evolvability deserve further epidemiological studies.IMPORTANCEAssigning the genuine natural viral host range may be uncertain without testing the susceptibility of primary cells. <i>Parvoviridae,</i> a family of ssDNA icosahedral viruses, harbors several members infecting humans, but only parvovirus B19 of the <i>Erythroparvovirus</i> genus shows tropism for human hematopoietic progenitors. Here, we evaluate the tropism of the MVMi and MVMp parvoviruses for humans, which are assumed to be mouse pathogens. We show that MVMp is remarkably cytotoxic for human primitive CD34+ and committed erythroid and myeloid hematopoietic progenitors. Infection of basal and bone marrow-humanized immunodeficient mice shows the emergence of viral strain-specific genetic changes at the capsid domain binding sialic-acid receptors, denoting adaptation to the respective host hematopoiesis. Although a large epidemiological survey failed to identify circulating MVMp sequences or antibodies in human populations, its high toxicity to human hematopoietic progenitors of different lineages and primitiveness and rapid evolutionary capacity demand in-depth characterization of its potential pathogenicity for humans.