In vivo models are critical for understanding the pathogenic mechanisms operating in viral diseases, and for evaluating therapeutic approaches to combat these diseases. Gene therapeutic strategies show promise for viral diseases such as AIDS; however, standard animal models do not demonstrate pathology following HIV-1 infection, and therefore, may be inappropriate for modelling gene therapy approaches to combat AIDS. We have established the SCID-hu mouse, which harbors a normally functioning human thymus, as a model for HIV-1-induced pathology and for exogenous human stem cell transfer. Purified human CD34+ progenitor cells, when introduced into human thymus/liver (Thy/Liv) implants in SCID-hu mice, develop into normal human T-lymphocytes. Furthermore, transduction of retroviral vectors into these cells prior to implantation results in human thymocytes which harbor and express vector sequences. In this proposal, we will optimize conditions to develop the SCID-hu mouse as a model to study human stem cell reconstitution and gene transfer in vivo. These studies will also explore the role of lymphoid stromal elements and the effect of HIV-1 infection on immune reconstitution.
The Specific Aims of this proposal are: 1. To define the parameters for efficient T-cell reconstitution by precursor cell transfer in the SCID-hu mouse model; 2. To determine the effect of HIV infection and gene transfer on non-T-cell thymus elements; and 3. To determine the effect of HIV infection on progenitor cell reconstitution. Our goals, in conjunction with the accompanying RO1 proposal, """"""""Modelling Gene Therapeutic Approaches in the SCID-hu Mouse"""""""" by Principal Investigator Chen, are to develop the SCID-hu system as a model to determine the in vivo efficacy of certain gene therapeutic approaches to combat HIV-1-induced pathology.
Showing the most recent 10 out of 31 publications
