Productive Infection of Human Cord Blood Stem Cells and Lineage Progenitors by Porcine Endogenous Retrovirus (PERV).

Endogenous retroviruses were once considered “junk DNA” and merely residual evolutionary genetic material. In the human system, recent reports have suggested a link between activation of human endogenous retroviruses (HERV) and certain diseases. Activation may be restricted to an up-regulation of viral specific transcripts or may involve gene translation with the assembly of virus-like particles (Morgan, Exp.Hem., 2004). Against this background of a possible link between activated endogenous retroviruses and disease, the potential risks of porcine to human transmission in the context of xenotransplantation becomes more plausible. The principal focus of this report was to determine the susceptibility of human primary cells to porcine endogenous retroviruses (PERV). Expression of a receptor for PERV has been described to be widespread in human tissues (Ericsson,PNAS,2003) and was expressed in hematopoietic stem cells and progenitors of our study. We exposed human umbilical cord blood (UCB) stem cells and cytokine-induced erythroid, myeloid and megakaryocytic progenitors to retroviral pseudotypes composed of replication competent wildtype PERV-NIH virions that also carry an MLV-based retroviral vector genome encoding β-galactosidase (β-gal) (Wilson, J. Vir., 2000; Harrison, J. Vir., 2004). Three days after exposure to PERV, cells were washed in order to remove unbound virus and assayed for viral RNA and DNA using quantitative PCR and RT-PCR (Argaw, J. Gen. Vir. 2002). Cell pellets from stem cells as well as lineage-induced cells were consistently positive for viral DNA and RNA and persisted during a kinetic study 3,5,6,and 7 days post-exposure to PERV. Control cells that were not exposed to PERV were negative in all parameters. There were no detectable adverse effects of PERV infection on cell proliferation or on terminal maturation of the progenitors of all three lineages. PERV infection does not require lineage commitment and provides a mechanism by which self-renewing stem cells may serve as an in vivo reservoir of virus in human bone marrow. Of note, the natural course of disease (anemia) of a related retrovirus, feline leukemia virus, also relies upon infection of hematopoietic progenitors in the bone marrow.