The pathogenesis of AIDS likely involves both the direct killing of infected CD4+ T cells and the induction of functional defects and apoptosis within the pool of uninfected lymphocytes. A consistent abnormality of lymphocytes from HIV-infected patients is a perturbation of the normal cell cycle control, which we have termed """"""""cell cycle disease"""""""" (CCD), that consists of (i) increased activation of the cyclin B/p34-cdc2 complex, and (ii) abnormal nucleolar structure with deregulation of nucleolin turnover. Since these abnormalities of CCD are exacerbated in vitro by mitogens and are associated with induction of apoptosis, we have proposed that the cell cycle dysregulation represents a link between increased activation/turnover and high levels of apoptosis of uninfected T lymphocytes observed in HIV-infected patients. Our preliminary data indicate that CCD can be corrected in vitro by treatment with IL-2. In addition, we have found that CCD is most prominent in vivo in the subset of patients who manifest persistent lymphocyte depletion despite HAART-induced suppression of viral replication. These observations suggest that analysis of the cell cycle perturbations might be able to help identify patients that could benefit from alternative, immune-based interventions, such as IL-2 and others, in addition to standard HAART, The overall goal of this project is to test the hypothesis that the CCD is a significant contributor to the pathogenesis of AIDS. We will perform: (i) a detailed cross-sectional study of HIV-infected individuals to study the relationship between cell cycle abnormalities and the main markers of HIV-disease progression, including the response to HAART; (ii) a study of CCD in non-human primates with both pathogenic (rhesus macaques) and non-pathogenic (sooty mangabeys) SIV-infection; and (iii) a longitudinal analysis of CCD inpatients treated with IL-2 plus HAART or HAART alone, to test the hypothesis that IL-2 therapy recapitulates in vivo the beneficial effects of in vitro IL-2 administration on the cell cycle abnormalities. These analyses could provide relevant information on the role played by the loss of cell cycle regulation in the pathogenesis of AIDS, and could help defining the rationale for additional, immune-based interventions in a subset of HAART-treated HIV-infected patients. ? ?
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