This component of the linked proposals has two general aims. The first is to supply the relevant animal models, the SCID-hu and hu-PBL SCID mouse, for study of the anti-HIV therapies to be tested. The second is to supply the relevant human cells, peripheral blood mononuclear cells and CD34+ bone marrow progenitor cells, for theses studies. C.B-17 scid/scid (SCID) mice have severely impaired humoral and cellular immunity and thus accept xenografts of human tissue. SCID mice reconstituted with either human hematopoietic elements (SCID-hu) or with human peripheral blood cells (hu-PBL SCID) may be infected with HIV. These models have served for study of the effects of antiretroviral agents in vivo in these reconstituted animals. These small animal are attractive in that they are relatively plentiful, easy to care for, and relatively inexpensive. Furthermore, unlike simian, rabbit or other animal models for HIV disease, infection occurs in human hematopoietic cells, and infection occurs with HIV, not some related retrovirus. Thus, a convenient model is presented to initiate the in vivo component of our studies of the feasibility of using retroviruses and other vectors for delivery of diphtheria toxin A chain as a gene therapy for HIV disease. Mice will be engrafted wit transduced peripheral blood cells to assess their ability to resist HIV infection. Transduced CD34+ progenitor cells will be transplanted to assess the ability of these cells to differentiate into mature lymphoid elements and retain the transduced DT- A gene, and HIV resistance.
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