No abstract

Murine AIDS (MAIDS) is a disease that shows many similarities to human HIV infection. The etiological agent of MAIDS is a defective murine leukemia virus that seems to be able to induce disease in the absence of viral replication. This animal model has been useful in stimulating the search of answers to questions and the formation of new hypotheses related to human AIDS. The monovalent cation lithium can influence a number of immunohematopoietic cell types and cellular processes where proliferation and differentiation occur. We describe here the result of in vivo studies investigating the effect of lithium treatment on MAIDS-infected mice. Viral control and lithium-treated animals were monitored for survival and development of MAIDS pathology. MAIDS animals treated with lithium demonstrated a marked reduction in their development of lymphadenopathy and splenomegaly. Both MAIDS control and lithium-treated virus-infected mice developed evidence of lymphoma; however, the involvement was much more massive both at the gross and microscopic levels in the MAIDS control compared with the lithium-treated mice. These data suggest that lithium may be effective in modulating murine immunodeficiency virus infection and raise important questions related to the potential role lithium may play in the pathophysiological processes associated with retroviral infections.

Murine acquired immunodeficiency syndrome (MAIDS) induced by defective LP-BM5 murine leukemia virus (MuLV) is a disease with many similarities to human AIDS. Our previous studies demonstrated that the depressed hematopoiesis observed in LP-BM5-infected marrow cultures could be attributed to a defective hematopoietic stroma. We report now the generation of permanent stroma cell lines from noninfected and LP-BM5-infected marrow cultures. Retrovirus infection was confirmed by the polymerase chain reaction for detecting viral genome expression of the p12 envelope glycoprotein. The ability of these cell lines to support in vitro hematopoiesis was evaluated. The results demonstrated that when cocultured with normal or infected nonadherent mononuclear cells, noninfected cell lines efficiently supported the production of hematopoietic progenitors, whereas in virus-infected cell lines production of both normal and virus-infected progenitors was suppressed. Expression of cytokine genes in stromal cell lines was also examined. All cell lines expressed equivalent levels of transcripts for interleukin (IL)-1β IL-2, IL-3, IL-6, IL-7, IL-10, interferon, tumor necrosis factor-α and stem cell factor. However, infection was associated with higher expression of IL-4 and transforming growth factor-β1. These findings demonstrate that infected stomal cell lines generate a defective hematopoietic microenvironment to produce altered cytokine expression and faulty hematopoiesis. Further characterization of these defective cell lines should assist elucidation of the mechanism(s) whereby retroviruses alter hematopoiesis ultimately leading to the generation of immunodeficiency.

We report here the results of studies examining the ability of zidovudine (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) immunodeficiency virus (10 micrograms total protein) intraperitoneally. Five weeks after viral infection, mice were sacrificed and marrow was harvested from normal non-virus-infected and virus-infected animals. LTMC were established in the presence or absence of dose escalation of AZT, that is, 10(-6), 5 x 10(-7), and 10(-7) M in vitro. Compared with controls prepared from normal bone marrow, LTMC using MAIDS-infected marrow failed to establish and subsequently release supernatant-derived mononuclear cells. 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 were all depressed and none were observed after 5 weeks of culture. Treatment with AZT failed to reverse this depression of stem cell progenitors. Microscopic examination of cultures at 10 weeks demonstrated a failure of MAIDS-LTMC to establish an adequate stromal layer compared to LTMC prepared form non-virus-infected controls. This data indicate that LP-BM5 MuLV infection alters the establishment of a normal functioning hematopoietic microenvironment or stroma. Acknowledging that important differences between MAIDS and human AIDS exist, the implications of these findings concerning the establishment of the immunodeficiency disease state in human immunodeficiency virus infection is discussed.

The drug zidovudine (AZT), a synthetic thymidine analogue, has been used in the treatment of acquired immunodeficiency syndrome (AIDS). Clinical use of zidovudine has induced haematopoietic toxicity manifested by anaemia, neutropenia, and overall bone marrow suppression. The monovalent cation lithium has been shown to be an effective agent capable of modulating several aspects of haematopoiesis such as the induction of neutrophilia, thrombopoiesis, and protection against suppression of hematopoietic progenitor stem cells following exposure to anti-cancer drugs and/or radiation at doses commonly used in the treatment of malignant disease. We report here the result of studies designed to evaluate the effectiveness of lithium in reversing zidovudine-induced haematopoietic suppression when administered to normal mice in vivo in the presence of dose-escalation zidovudine. Lithium carbonate (Li2CO3) reversed zidovudine toxicity as measured by increases in peripheral WBC, platelets, and CFU-GM and CFU-Meg haematopoietic progenitors; however lithium was insufficient in reversing the reduction of erythropoiesis associated with zidovudine use in vivo. These results further confirm the effective use of lithium to reverse the development of myelosuppression and thrombocytopenia associated with the anti-viral drug zidovudine, but is less effective in ameliorating the induction of anaemia.