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IL2-R alpha chain inhibitory factor (p29) produced by HIV-infected macrophages: cell target and mode of action
A Ammar1, A M Bertoli, S Chouaib
1Oncogenese Appliquee, INSERM U268, Hôpital Paul Brousse, Villejuif, France.
Abstract:
We recently reported that HIV-infected adherent cells spontaneously produce a 29-kDa protein (p29), most probably of nonviral origin, which inhibits expression of the IL2R alpha chain on activated normal T cells. Studying the mode of action of this molecule, we observed that monocyte depletion of normal PBMC either by plastic adherence or by complement-mediated cytotoxicity using macrophage-specific monoclonal antibodies abrogated the inhibitory effect of p29. The biological activity of p29 in adherent cell-depleted PBMC could be restored either with rIL1 or with as little as 10(5) autologous adherent cells/ml. Moreover, p29 could not inhibit IL1 biologic activity, nor its binding to IL1 receptor. In addition, p29 could not inhibit the production of IL1 and TNF alpha by normal adherent cells. Positive and negative cell sorting of normal T cells as well as two-color immunofluorescence studies revealed that CD8+ subsets are the main cell targets of p29, which also mediated an impaired generation of alloantigen-specific CTL. Conversely, only a slight inhibitory activity could be detected in highly purified CD4+ cells. Our findings suggest that HIV-induced production of p29 inhibitory factor by adherent cells may be involved in mechanisms responsible for some of the impaired cytotoxic functions observed in AIDS patients.
Insights
Human immunodeficiency virus (HIV)-infected cells produce a protein (p29) that inhibits T cell function. This protein
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Human immunodeficiency virus (HIV) infection is associated with impaired immune cell function.
- Adherent cells in HIV-infected individuals can produce a nonviral 29-kDa protein (p29).
- This protein (p29) has been shown to inhibit the expression of the IL2R alpha chain on activated T cells.
Purpose of the Study:
- To investigate the mechanism of action of the HIV-induced p29 protein.
- To identify the specific immune cell targets and functional consequences of p29 activity.
- To explore the role of p29 in the immune dysfunction observed in Acquired Immunodeficiency Syndrome (AIDS).
Main Methods:
- Depletion of monocytes from peripheral blood mononuclear cells (PBMCs) using plastic adherence or complement-mediated cytotoxicity.
- Restoration of p29 activity using recombinant Interleukin-1 (rIL1) or autologous adherent cells.
- Cell sorting of T cell subsets (CD4+ and CD8+) and two-color immunofluorescence.
- Assessment of alloantigen-specific cytotoxic T lymphocyte (CTL) generation.
Main Results:
- Monocyte depletion abrogated the inhibitory effect of p29, which could be restored by adherent cells or rIL1.
- p29 did not inhibit IL1 activity, receptor binding, or the production of IL1 and TNF alpha.
- CD8+ T cell subsets were identified as the primary targets of p29, leading to impaired CTL generation; CD4+ cells showed minimal inhibition.
Conclusions:
- HIV-induced p29 production by adherent cells may contribute to impaired cytotoxic functions in AIDS patients.
- p29's mechanism involves targeting CD8+ T cells, impacting adaptive immune responses.
- Understanding p29's role offers insights into HIV-associated immunopathogenesis.