FAILURE TO ESTABLISH LONG-TERM MARROW CULTURES FROM IMMUNODEFICIENT MICE (MAIDS) - EFFECT OF ZIDOVUDINE IN-VITRO

We report here the results of studies examining the ability of zidovud ine (AZT) to influence the establishment and maintenance of long-term marrow cultures (LTMC) using marrow from murine immunodeficient mice ( MAIDS). Normal C57BL6 mice were infected with LP-BM5 (MuLV) immunodefi ciency virus (10 mug total protein) intraperitoneally. Five weeks afte r viral infection, mice were sacrificed and marrow was harvested from normal non-virus-infected and virus-infected animals. LTMC were establ ished in the presence or absence of dose escalation of AZT, that is, 1 0(-6), 5 X 10(-7), and 10(-7) M in vitro. Compared with controls prepa red from normal bone marrow, LTMC using MAIDS-infected marrow failed t o establish and subsequently release supernatant-derived mononuclear c ells. The addition of AZT was ineffective in either establishing LTMC or consistently producing mononuclear cells. Measurements of erythroid (BFU-E), myeloid (CFU-GM), and megakaryocyte (CFU-Meg) precursors wer e all depressed and none were observed after 5 weeks of culture. Treat ment with AZT failed to reverse this depression of stem cell progenito rs. Microscopic examination of cultures at 10 weeks demonstrated a fai lure of MAIDS-LTMC to establish an adequate stromal layer compared to LTMC prepared form non-virus-infected controls. This data indicate tha t LP-BM5 MuLV infection alters the establishment of a normal functioni ng hematopoietic microenvironment or stroma. Acknowledging that import ant differences between MAIDS and human AIDS exist, the implications o f these findings concerning the establishment of the immunodeficiency disease state in human immunodeficiency virus infection is discussed.