Our understanding of the complexities of pathogenic mechanisms of HIV disease is still evolving. This project has been investigating the immunologic consequences of HIV envelope glycoprotein mediated ligation of CD4 molecules. The underlying hypothesis is that HIV can lead to aberrant CD4 signaling which constitutes a key pathogenic mechanism in HIV infection, leading to aberrant cytokine secretion and contributing to immunologic anergy, quantitative loss of lymphocytes by apoptosis and virus upregulation. During the previous funding period we demonstrated that simple CD4 ligation by HIV gp120 or by anti-CD4 antibody resulted in a state of functional unresponsiveness in CD4+T cells, whereas if the CD4 molecules were crosslinked (XL), the cells were primed from apoptosis. Importantly we demonstrated that CD4 crosslinking of normal peripheral blood mononuclear cells led to induction of Fas antigen upregulation and apoptosis in CD4 T cells. The latter process was associated with the induction of cytokines TNF-alpha and Interferon-gamma (without IL-2 or IL- 4). We propose to continue these studies with the aim of understanding the immunologic and virologic effects of CD4 ligation in HIV disease pathogenesis.
Our specific aims are to elucidate the mechanisms oc CD4 crosslinking (CD4XL)-induced T cell apoptosis with the goal of studying interactions and relationship between the apoptosis promoting molecules. Fas and Fas-ligand (Fas-L). and the apoptosis repressor system made up of the Bcl-2 proteins, the role of monocyte/macrophages in the induction of T cell apoptosis, the regulatory role of cytokines in this process and finally to investigate intracellular signaling that is associated with Fas'Fas-L interaction. We also observed that CD4XL in patient cells leads to HIV upregulation. A critical question being asked is the mechanism by which immunologic forces drive replication. Studies in patients will test the proposed model of CD4XL-induced induction of apoptosis and HIV upregulation. Attempts will be made to reverse or prevent CD4XL-induced harmful effects. These findings have relevance for understanding AIDS pathogenesis and for designing immune based therapeutic strategies and vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028281-09
Application #
2671952
Study Section
Special Emphasis Panel (ZRG5-ARRC (01))
Project Start
1989-03-01
Project End
2001-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
9
Fiscal Year
1998
Total Cost
Indirect Cost
Name
North Shore University Hospital
Department
Type
DUNS #
City
Manhasset
State
NY
Country
United States
Zip Code
11030
McCloskey, Thomas W; Haridas, Viraga; Pontrelli, Lucy et al. (2004) Response to superantigen stimulation in peripheral blood mononuclear cells from children perinatally infected with human immunodeficiency virus and receiving highly active antiretroviral therapy. Clin Diagn Lab Immunol 11:957-62
Kharbanda, Monica; McCloskey, Thomas W; Pahwa, Rajendra et al. (2003) Alterations in T-cell receptor Vbeta repertoire of CD4 and CD8 T lymphocytes in human immunodeficiency virus-infected children. Clin Diagn Lab Immunol 10:53-8
McCloskey, Thomas W; Haridas, Viraga; Pahwa, Rajendra et al. (2002) T cell receptor V beta repertoire of the antigen specific CD8 T lymphocyte subset of HIV infected children. AIDS 16:1459-65
Chavan, S; Bennuri, B; Kharbanda, M et al. (2001) Evaluation of T cell receptor gene rearrangement excision circles after antiretroviral therapy in children infected with human immunodeficiency virus. J Infect Dis 183:1445-54
McCloskey, T W; Kohn, N; Lesser, M et al. (2001) Immunophenotypic analysis of HIV-infected children: alterations within the first year of life, changes with disease progression, and longitudinal analyses of lymphocyte subsets. Cytometry 46:157-65
Niehues, T; McCloskey, T W; Ndagijimana, J et al. (2001) Apoptosis in T-lymphocyte subsets in human immunodeficiency virus-infected children measured immediately ex vivo and following in vitro activation. Clin Diagn Lab Immunol 8:74-8
Chavan, S; Kodoth, S; Pahwa, R et al. (2001) The HIV protease inhibitor Indinavir inhibits cell-cycle progression in vitro in lymphocytes of HIV-infected and uninfected individuals. Blood 98:383-9
McCloskey, T W; Haridas, V; Pahwa, R et al. (2001) Human immunodeficiency virus gag and pol-specific CD8 T cells in perinatal HIV infection. Cytometry 46:265-70
Krilov, L R; McCloskey, T W; Harkness, S H et al. (2000) Alterations in apoptosis of cord and adult peripheral blood mononuclear cells induced by in vitro infection with respiratory syncytial virus. J Infect Dis 181:349-53
Tateyama, M; Oyaizu, N; McCloskey, T W et al. (2000) CD4 T lymphocytes are primed to express Fas ligand by CD4 cross-linking and to contribute to CD8 T-cell apoptosis via Fas/FasL death signaling pathway. Blood 96:195-202

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