Grant: Operating Grant - PA: HIV/AIDS Research Initiative - Biomedical/Clinical Stream

A major obstacle to the study AIDS pathogenesis and the development of effective treatments is the lack of a suitable small animal model. However, we have overcome this obstacle by generating transgenic (Tg) mice that express HIV-1 Nef protein in the same immune cells normally infected in humans. These mice developed an AIDS-like disease remarkably similar to the clinical and pathological features of human AIDS. These include premature death, weight loss, a gradual destruction of the immune system, characterized by thymic and lymphoid organ atrophy, altered thymic development of CD4+ T cells and organ diseases in lung, heart and kidney. Functions of all immune cells in these Tg mice were shown to be impaired and this led to increased susceptibility to opportunistic infection. These Nef Tg mice have provided an excellent animal model to facilitate the molecular dissection of the underlying mechanisms of Nef involvement in HIV-1 pathogenesis. We believe that the Nef protein promotes the pathogenesis of the AIDS-like disease by modifying the functions of multiple distinct Nef expressing cell lineages, which collaborate together to induce pathology. In order to understand the complex nature of this disease, it is essential to dissect the role of each of these immune cells in disease development. Therefore, among the goals of this proposal is to identify the physiologically relevant targets of the Nef action and to understand how HIV-1 Nef protein could mediate the pathology in vivo. In conclusion, we have successfully modeled in mice, pathophysiology observed in HIV-1 infected patients. This work has significantly increased our understanding of HIV-1 Nef pathogenesis in vivo. Given the high degree of similarity between murine and human physiology, the knowledge gained from these studies will be directly applicable to understanding the human diseases that result from HIV infection and will open new avenues to combat the virus through novel anti-HIV Nef therapies.