Project: Research project

Project Details


DESCRIPTION (Adapted from the applicant's abstract) After exposure of an
individual to an inoculum of HIV-1, an infectious cycle is initiated that
leads to systemic dissemination of HIV-1 and HIV-1-infected cells into
lymphoid organs and bone marrow. The presence of HIV-l in the bone marrow
may be the etiology of hematological abnormalities seen in HIV-1-infected
patients. Ineffective hematopoiesis may result from a direct effect of
HIV-1 on stem/progenitor cells, stromal cells or mature cells present in
the bone marrow. This effect may be mediated by infection of cells by
HIV-1, a direct toxic effect of HIV-1 encoded proteins, or by the
HIV-1-mediated suppression of stimulatory cytokines or induction of
suppressive cytokines. The applicants have recently described a modified
SCID-hu mouse model for disseminated HIV-l infection (Kollmann et al. J.
Exp. Med., 1994; 179:513-522) made by, first, implanting human fetal thymus
and liver in SCID mice. Significant numbers of human T cells were detected
in the peripheral blood, spleens and lymph nodes of these mice. Second,
after injecting HIV-1 into these SCID-hu mice, either into the implanted
human liver or intraperitoneally, disseminated HIV infection was observed.
In addition to this model for in vivo HIV-l-infection of human T cells, the
applicants have also developed a model, BM-SCID-hu mice, that can be used
to study the in vivo HIV-l infection of human monocytes and B cells. For
this second model, cultured human fetal bone marrow cells were transplanted
into irradiated SCID mice, resulting in significant engraftment with human
precursor cells and reconstitution of the peripheral lymphoid compartment
with human B cells and monocytes. Administration of extraneous human
cytokines was not required. In summary, these transplantations generated
mice wherein human hematopoiesis occurs in SCID mouse bone marrow,
resulting in a peripheral lymphoid compartment populated with human T
cells, B cells and monocytes. The applicants propose to utilize these
models to study the effect of acute and chronic HIV-1 infection on human
hematopoiesis in vivo. In addition, they propose to investigate potential
effectiveness of various interventions to reverse the negative effects of
HIV-1 on hematopoiesis.
Effective start/end date9/30/948/31/99


  • Transplantation


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