A large number of studies on hematopoietic progenitor cells either from patients with AIDS or from normal volunteers infected by HIV-1 ex-vivo, have clearly indicated that although a small population of CD34+ marrow cells can be infected by HIV-1, stem cells and progenitors are not readily infected in vitro and are almost never infected in vivo. However, experiments on myeloid failure in AIDS indicate that auxiliary cells of the marrow stroma, some of which can be infected by HIV-1, fail to support normal myeloid hematopoiesis, suggesting that auxiliary cells in the microenvironment, and not stem cells and progenitors, may be the primary cell population that accounts for HIV-1 induced hematopoietic dysfunction. Since bone marrow stromal cell progenitors, including microvascular endothelial cells, can express CD34, we tested the hypothesis that bone marrow microvascular endothelial cells from some patients with AIDS were the HIV-1 infected CD34+ population. Recently, using bone marrow cells from normal volunteers and from three consecutive AIDS patients, the applicants have discovered: (1) conditions that favor long-term cultures of bone marrow stromal cells enriched in microvascular endothelial cells (MVEC stroma), some of which express CD34; (2) that MVEC derived from all three patients with AIDS were productively infected by HIV-1 while no other stromal cell type was infected; and (3) hematopoietic growth factor gene expression induced by IL-I in HIV-1-infected MVEC stroma (compared to normal stroma enriched for MVEC) was quantitatively suppressed. The applicant propose a model of hematopoietic dysfunction in HIV-1 infection in which infected bone marrow MVEC cause, directly or indirectly, a decline in the supportive function of the marrow stroma such that hematopoiesis is inhibited. The application is designed to fully test this model by; (a) determining the incidence and stage-relatedness of HIV-1 infection of bone marrow MVEC in seropositive patients, (b) quantifying the capacity of HIV-1 infected MVEC- stroma to support growth of committed progenitor cells, (c) quantifying constitutive and induced expression of genes encoding hematopoietic growth factors, adhesion molecules, and mitotic inhibitors in HIV-1 infected stromal cells, and (d) confirming the cause-and-effect relationship between specific dysfunctions observed in our studies and HIV-1 per se, using genetic loss-of- function and gain- of-function analyses.
| Moses, A; Nelson, J; Bagby Jr, G C (1998) The influence of human immunodeficiency virus-1 on hematopoiesis. Blood 91:1479-95 |
| Moses, A V; Williams, S E; Strussenberg, J G et al. (1997) HIV-1 induction of CD40 on endothelial cells promotes the outgrowth of AIDS-associated B-cell lymphomas. Nat Med 3:1242-9 |
| Moses, A V; Williams, S; Heneveld, M L et al. (1996) Human immunodeficiency virus infection of bone marrow endothelium reduces induction of stromal hematopoietic growth factors. Blood 87:919-25 |
