Evidence for a Human Immunodeficiency Virus Type 1-Mediated Suppression ofUninfected Hematopoietic (CD34+) Cells in AIDS Patients

Abstract

Hematopoietic progenitor (CD34+) cells were purified from the bone marrow of 6 human immunodeficiency virus (HIV) type 1-seropositive cytopenic patients and 10 healthy donors. HIV-1-seropositive patients showed a reduced number of granulocyte/macrophage, erythroid, and megakaryocyte progenitors and also a progressive and significant decline of numbers of CD34+ cells in liquid culture, which did not result from a productive or latent HIV-1 infection of CD34+ cells. However, all HIV-1-seropositive patients showed signs of active viral replication at the bone marrow level. Moreover, virus isolates from 3 HIV-1-seropositive patients showed a dose-dependent inhibition on growth of normal CD34+ cells. This suppressive activity was almost completely reversed by incubating the virus isolates with an anti-gp120 polyclonal antibody before adding to normal CD34+ cells.

Intracellular immunization of human fetal cord blood stem/progenitor cells with a ribozyme against human immunodeficiency virus type 1.

“…Because pediatric AIDS progresses more rapidly than the adults' disease (80% infected infants become symptomatic in the first year) (25), in vivo gene therapy efficacy can be assessed more rapidly in this population. The issue of whether CD34+ cells can be infected by HIV is still controversial, but it is generally agreed that the majority of CD34+ stem cells are not infected (26,27). Our present and previous data suggest that CD34+ cells can be transduced with the ribozyme gene, which inhibits both the establishment of infection (5) …”

Impaired progenitor cell function in HIV-negative infants of HIV-positive mothers results in decreased thymic output and low CD4 counts

“…Furthermore, thymic abnormalities are described in fetuses aborted from HIV-positive women even in the absence of thymic HIV infection. 42 Impaired progenitor cell function in HIV-positive patients has been reported, [11][12][13][14][15][16][17][18] the number of immature progenitors is decreased, 11,15 and progenitors from HIV-infected patients display diminished T-cell generation capacity when examined in FTOCs. 9,10 In the present study, the decreased red blood cell count and the lower CD4 counts indicated that progenitor cell function was impaired in infants of HIVpositive mothers.…”

“…10,11,and 18) and 3 controls were analyzed for ability to differentiate into T cells in thymic organ cultures.…”

“…8 HIV particles as well as HIV proteins are known to inhibit progenitor cell function and to cause progenitor cell apoptosis which, in turn, would lead to both hematologic and immunologic deficiencies in the infants. [9][10][11][12][13][14][15][16][17][18] Furthermore, cytokine imbalance between Th1-and Th2-type cytokines has been suggested in HIV-positive individuals. [19][20][21] Such an imbalance in pregnant HIV-positive women might also cause cytokine imbalance in the fetus, resulting in immunologic deficiencies.…”

T Cell Dynamics in HIV-1 Infection

“…However, the progenitors from the infected individual were I unable to develop on bone marrow stroma from the uninfected individual. Bone marrow from HIV-1-infected individuals was shown to have diminished capacity to develop cells of the granulocyte, erythrocyte, and megakaryocyte lineages in in vitro colony assays (Zauli et al, 1992(Zauli et al, , 1996Steinberg et al, 1991). Because the T cell lineage is derived from the same common precursor as these lineages, it was reasonable to assume that development of this lineage would also be affected.…”