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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI052755-01A1
Application #
6591190
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Roe, Joanad'Arc C
Project Start
2003-05-01
Project End
2007-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
1
Fiscal Year
2003
Total Cost
$400,000
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Brenchley, Jason M; Paiardini, Mirko; Knox, Kenneth S et al. (2008) Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood 112:2826-35
Estes, Jacob D; Gordon, Shari N; Zeng, Ming et al. (2008) Early resolution of acute immune activation and induction of PD-1 in SIV-infected sooty mangabeys distinguishes nonpathogenic from pathogenic infection in rhesus macaques. J Immunol 180:6798-807
Dunham, Richard M; Cervasi, Barbara; Brenchley, Jason M et al. (2008) CD127 and CD25 expression defines CD4+ T cell subsets that are differentially depleted during HIV infection. J Immunol 180:5582-92
Gordon, Shari N; Klatt, Nichole R; Bosinger, Steven E et al. (2007) Severe depletion of mucosal CD4+ T cells in AIDS-free simian immunodeficiency virus-infected sooty mangabeys. J Immunol 179:3026-34
Pandrea, Ivona; Apetrei, Cristian; Gordon, Shari et al. (2007) Paucity of CD4+CCR5+ T cells is a typical feature of natural SIV hosts. Blood 109:1069-76
Apetrei, Cristian; Gautam, Rajeev; Sumpter, Beth et al. (2007) Virus subtype-specific features of natural simian immunodeficiency virus SIVsmm infection in sooty mangabeys. J Virol 81:7913-23
Dunham, Richard; Pagliardini, Paola; Gordon, Shari et al. (2006) The AIDS resistance of naturally SIV-infected sooty mangabeys is independent of cellular immunity to the virus. Blood 108:209-17
Paiardini, M; Cervasi, B; Sumpter, B et al. (2006) Perturbations of cell cycle control in T cells contribute to the different outcomes of simian immunodeficiency virus infection in rhesus macaques and sooty mangabeys. J Virol 80:634-42
Brenchley, Jason M; Price, David A; Schacker, Timothy W et al. (2006) Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12:1365-71

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