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 thymopoiesis. It has been constructed by engrafting fragments of human fetal liver and thymus into the immunodeficient C.B-17 scid/scid (SCID) mouse. 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 mechanisms of HIV-I infection in vivo, and to test therapeutic modalities such as anti-HIV-1 drugs and haematopoietic stem cell (HSC)-based gene therapy. 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 replication and therapy. Unique HIV-I determinants have been identified which are required for replication in the Thy/Liv organ but not for replication in PBMC or in T cell lines In vitro. The mechanism of HIV-I induced thymus depletion is not clear. It is correlated with high levels of HIV-I replication. Both direct and indirect mechanisms may be involved. In addition to preclinical evaluation of anti- HIV-1 drugs, the SCID-hu Thy/Liv mouse has also been successfully used to test the feasibility 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 information for understanding pathogenesis and designing therapeutic interventions against HIV-I infection in humans, especially in paediatric patients. (C) 1997 by John Wiley & Sons, Ltd.