application abstract) Apoptosis, or programmed cell death, of peripheral blood lymphocytes has received attention as a possible mechanism whereby HIV-1 may deplete T lymphocytes. Apoptosis of lymphocytes in the setting of HIV-l infection could conceivably arise by several mechanisms, including CD4 cross-linking, upregulation of Fas (APO1, CD95) the cellular receptor and transducer of the """"""""death signal"""""""", and/or upregulation of Fas ligand. A deeper understanding of the biology of Fas has revealed a non-apoptotic, regulatory function for Fas in lymphocyte development, which suggests possible mechanisms other than cell death by which virus may exert pathological effects. The central hypthesis of this study is that HIV-1 may alter the regulation of Fas and its ligand in central hematolymphoid organs, and thereby interfere with lineage development. Employing SCID-hu Thy/Liv and SCID-hu Bone systems as models of hemetopoiesis and of HIV-1 infection, experiments will first address the effects of HIV-1 infection on the expression of Fas on fluorescence-sorted subpopulations of hematopoietic and lymphocyte progenitor cells. The funcitonal consequences of HIV-1-induced alterations of Fas will then be studied using assays of hematopoietic funciton, proliferation, and TCR signaling.
Jenkins, M; Keir, M; McCune, J M (2000) A membrane-bound Fas decoy receptor expressed by human thymocytes. J Biol Chem 275:7988-93 |
Jenkins, M; Keir, M; McCune, J M (1999) Fas is expressed early in human thymocyte development but does not transmit an apoptotic signal. J Immunol 163:1195-204 |
Jenkins, M; Hanley, M B; Moreno, M B et al. (1998) Human immunodeficiency virus-1 infection interrupts thymopoiesis and multilineage hematopoiesis in vivo. Blood 91:2672-8 |