BONE-MARROW FAILURE BY CYTOMEGALOVIRUS IS ASSOCIATED WITH AN IN-VIVO DEFICIENCY IN THE EXPRESSION OF ESSENTIAL STROMAL HEMOPOIETIN GENES

Bone marrow (BM) failure associated with cytomegalovirus (CMV) infecti on is a feared complication after clinical BM transplantation. Experim ents in long-term BM cultures have indicated that BM stromal cells (BM SC) are targets of productive CMV infection, but an in situ infection of BM stroma remained to be documented, and the pathomechanism is open to question. Here we describe a murine in vivo model of lethal CMV ap lastic anemia (CMV-AA). The reconstitution of hematopoietic progenitor cells expressing stem cell factor (SCF) receptor was found to be defe ctive in CMV-AA. While murine CMV replication in permissive parenchyma l tissues is cytolytic, the hematopoietic cord was found to be a site of very limited virus production with foci of reticular BMSC expressin g the intranuclear viral IE1 protein, but with only a few BMSC positiv e for viral genome in the in situ hybridization. XX-XY BM chimeras wer e established in order to quantitate Y-chromosome-tagged BMSC by a PCR specific for the male-sex-determining gene Tdy. This approach reveale d that murine CMV infection is not associated with a significant loss of BMSC. Despite the physical integrity of the stromal network the fun ctional integrity of the stroma was impaired. While housekeeping genes were expressed normally in BMSC of infected mice, the expression of g enes encoding the essential hemopoietins SCF, granulocyte colony-stimu lating factor, and interleukin-6 was markedly reduced. In conclusion, the mechanism of BM failure is not a stromal lesion but an insufficien t stromal function. These findings explain CMV-AA as a manifestation o f multiple hemopoietin deficiency.