PATHOGENESIS OF HIV INFECTION

After exposure of an individual to an inoculum of HIV-1, and infectious cycle is initiated that leads to systemic dissemination of HIV-1 and HIV- 1-infected individuals between the very active HIV-1 infection observed in lymph nodes and the low degree of HIV-1 infection seen in peripheral blood. A s consequence of this dichotomy, examining the peripheral blood of HIV-1 infected individuals will not indicate the effects of therapeutic interventions on the high degree of covert HIV-1 replication occurring in the lymphoid tissues. We have recently described a modified SCID-hu mouse model for disseminated HIV-1 infection consisting of human fetal thymus and liver implanted in SCID mice. Significant numbers of human T cells were detected in the peripheral blood, spleens and lymph nodes of these mice and disseminated HIV infection was observed after either intraimplant injection or intraperitoneal inoculation of HIV-1 into these SCID-hu mice. In addition to this model for in vivo HIV-1- infection of human T cells, we have also developed a model, BM-SCID-hu mice, that can be used to study the in vivo HIV-1-infection of human monocytes and BM-SCID-hu mice, that can be used to study the in vivo HIV- 1 infection of human monocytes and B cells. After transplantation of irradiated SCID mice with cultured human fetal bone marrow cells, the bone marrow of these BM-SCID-hu mice become significantly engrafted with human precursor cells independent of the administration of extraneous human cytokines and the peripheral lymphoid compartment of these mice are reconstituted with human B cells and monocytes. By transplanting SCID mice implanted with human fetal thymus and liver with human fetal bone marrow, we have generated mice wherein human hematopoiesis is occurring in the mouse bone marrow and the peripheral lymphoid compartment is populated with human T cells, B cells and monocytes. Therefore, we propose to utilize these animal models to study the pathogenesis of acute and chronic HIV-1 infection in vivo and to investigate the effects of various anti-HIV interventions on disseminated HIV-infection present in their peripheral blood, lymphoid compartment, thymus and bone marrow of these mice.