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.
