HUMAN CYTOMEGALOVIRUS SUPPRESSION OF AND LATENCY IN EARLY HEMATOPOIETIC PROGENITOR CELLS

Bone marrow cells (BMC) are involved in the pathogenesis of human cyto megalovirus (HCMV) infections, and the hematopoietic cells are probabl e sites of HCMV latency in healthy donors. In vitro studies have indic ated both a direct inhibitory effect of HCMV on proliferation and diff erentiation of myeloid bone marrow progenitors and an impairment of bo ne marrow stroma cell function by HCMV. The purpose of the present stu dy was to establish whether the suppressing effect could be limited to subsets of immature CD34(+) BMC and to investigate the role of immatu re cell populations as possible sites of HCMV latency. CD34(+) cells f rom healthy HCMV-seropositive and -seronegative donors were sorted acc ording to the expression of HLA-DR (CD34(+)HLA-DR(+) and CD34(+)HLA-DR (-) cells). The progenitor growth of hematopoietic progenitor cells fr om seronegative donors was examined by colony and single-cell assays a fter in vitro infection with HCMV. To determine the susceptibility of the CD34(+) cells to HCMV infection in vitro and in vivo, cells of bot h subsets from seronegative and seropositive donors were analyzed for the presence of HCMV DNA by polymerase chain reaction. HCMV infection in vitro inhibited the interleukin-1 alpha (IL-1 alpha)-, IL-3-, granu locyte colony-stimulating factor-, granulocyte-macrophage colony-stimu lating factor-, and stem cell factor-induced proliferation in single-c ell assays of CD34(+) HLA-DR(-) cells by 34%. In contrast, the colony growth of the CD34(+)HLA-DR(+) subset was suppressed in cells from onl y 3 of the 8 donors, However, in vitro HCMV infection of the CD34(+)HL A-DR(+) progenitor cells inhibited the proliferation of all donors tes ted when hematopoietic growth factors were used individually to promot e progenitor growth. In addition, the formation of burst-forming units -erythroid and colony-forming units-granulocyte, erythrocyte, monocyte , megakaryocyte was reduced 40% to 60% by HCMV in vitro. In contrast, the growth of high proliferative potential colony-forming cells was no t inhibited after in vitro HCMV infection. Furthermore, HCMV DNA was d etected in both CD34(+)HLA-DR(-) and CD34(+)HLA-DR(+) progenitors from in vitro-infected HCMV-seronegative donors and cells from HCMV-seropo sitive donors. Taken together, the early progenitors defined as CD34()HLA-DR(-) and CD34(+)HLA-DR(+) are directly suppressed in their proli feration by HCMV in vitro, and hematopoietic stem cells are also sites of HCMV latency in healthy HCMV-seropositive donors. (C) 1996 by The American Society of Hematology.