HIV-1 PATHOGENESIS AND THERAPEUTIC INTERVENTION IN THE SCID-HU THY LIV MOUSE - A MODEL FOR PRIMARY HIV-1 INFECTION IN THE HUMAN THYMUS/

The SCID-hu Thy/Liv mouse is a model for the analysis of human thymopo iesis. It has been constructed by engrafting fragments of human fetal liver and thymus into the immunodeficient C.B-17 scid/scid (SCID) mous e. The resulting 'Thy/Liv' organ promotes long-term differentiation of human T cells. Given the apparently normal physiology of the SCID-hu Thy/Liv organ, it has been used to explore the pathophysiologic mechan isms of HIV-I infection in vivo, and to test therapeutic modalities su ch as anti-HIV-1 drugs and haematopoietic stem cell (HSC)-based gene t herapy. In this review, I will summarise what we have learned from the SCID-hu Thy/Liv model, with a focus on recent findings in HIV-I repli cation and therapy. Unique HIV-I determinants have been identified whi ch are required for replication in the Thy/Liv organ but not for repli cation in PBMC or in T cell lines In vitro. The mechanism of HIV-I ind uced thymus depletion is not clear. It is correlated with high levels of HIV-I replication. Both direct and indirect mechanisms may be invol ved. In addition to preclinical evaluation of anti- HIV-1 drugs, the S CID-hu Thy/Liv mouse has also been successfully used to test the feasi bility of HSC-based gene therapy. A number of improved SCID-hu models have been constructed to meet different requirements. Using these SCID -hu Thy/Liv models, current/future efforts will provide insightful inf ormation for understanding pathogenesis and designing therapeutic inte rventions against HIV-I infection in humans, especially in paediatric patients. (C) 1997 by John Wiley & Sons, Ltd.