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Role of CD40-Dependent Down-Regulation of CD154 in Impaired Induction of CD154 in CD4⁺ T Cells from HIV-1-Infected Patients¹

Carlos S. Subauste^2,*,, Angela Subauste and Matthew Wessendarp^*

^* Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267; Departments of Ophthalmology and Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106; and Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109

CD40-CD154 interaction is pivotal for cell-mediated immunity. There are contradictory reports on whether HIV-1 infection impairs CD154 induction. The interaction between CD40 and CD154 is important not only because it results in activation of APCs but also because it controls CD154 by diminishing expression of this molecule. Compared with healthy controls, CD4⁺ T cells from HIV-1⁺ patients had impaired induction of CD154 when T cell activation was mediated by CD40⁺ APCs. In contrast, T cell activation in the absence of these cells resulted in normal CD154 expression. CD154 induction in HIV-1⁺ patients and controls were similar upon blockade of CD40-CD154 binding. Defective regulation of CD154 appeared to occur downstream of the control of mRNA levels because up-regulation of CD154 mRNA was not impaired by HIV-1 infection. This work identifies CD40 as a mediator of impaired CD154 induction in HIV-1 infection and explains why this defect was not detected by studies where T cell activation was triggered independently of CD40⁺ APCs. In addition, dysregulation of CD154 in HIV-1 infection likely contributes to immunodeficiency because diminished expression of CD154 induced by CD40 is of functional relevance, resulting in decreased dendritic cell maturation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant AI48406 (to C.S.S.).

² Address correspondence and reprint requests to Dr. Carlos S. Subauste, Departments of Ophthalmology and Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106. E-mail address: carlos.subauste{at}case.edu

³ Abbreviations used in this paper: X-HIM, X-linked hyper-IgM; VL, viral load; MFI, mean fluorescence intensity; SEB, staphylococcal enterotoxin B.