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Journal of Virology, February 2009, p. 1193-1200, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01023-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Engagement of the CD4 Receptor Affects the Redistribution of Lck to the Immunological Synapse in Primary T Cells: Implications for T-Cell Activation during Human Immunodeficiency Virus Type 1 Infection {triangledown}

Alice M. Nyakeriga,1 Carl J. Fichtenbaum,2 Jens Goebel,3 Stella A. Nicolaou,4 Laura Conforti,4 and Claire A. Chougnet1*

Divisions of Molecular Immunology,1 Nephrology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio 45229,3 Divisions of Infectious Diseases,2 Nephrology and Hypertension, University of Cincinnati Medical Center, Cincinnati, Ohio 452674

Received 15 May 2008/ Accepted 9 November 2008

Understanding the molecular mechanisms underlying dysregulated immune responses in human immunodeficiency virus type 1 (HIV-1) infection is crucial for the control of HIV/AIDS. Despite the postulate that HIV envelope glycoprotein gp120-CD4 interactions lead to impaired T-cell responses, the precise mechanisms underlying such association are not clear. To address this, we analyzed Lck and F-actin redistribution into the immunological synapse in stimulated human primary CD4+ T cells from HIV-1-infected donors. Similar experiments were performed with CD4+ T cells from HIV-uninfected donors, which were exposed to anti-CD4 domain 1 antibodies, as an in vitro model of gp120-CD4 interactions, or aldithriol-inactivated HIV-1 virions before stimulation. CD4+ T cells from HIV-infected patients exhibited a two- to threefold inhibition of both Lck and F-actin recruitment into the synapse, compared to cells from uninfected donors. Interestingly, defective recruitment of Lck was ameliorated following suppressive highly active antiretroviral therapy. Engagement of the CD4 receptor on T cells from HIV-uninfected donors before anti-CD3/CD28 stimulation led to similar defects. Furthermore, the redistribution of Lck into lipid rafts was abrogated by CD4 preengagement. Our results suggest that the engagement of CD4 by HIV gp120 prior to T-cell receptor stimulation leads to dysregulation of early signaling events and could consequently play an important role in impaired CD4+ T-cell function.

* Corresponding author. Mailing address: Division of Molecular Immunology, Cincinnati Children's Hospital Medical Research Center, 3333 Burnet Avenue, Mail location code 7021, Cincinnati, OH 45229. Phone: (513) 636-8847. Fax: (513) 636-5355. E-mail: Claire.chougnet{at}cchmc.org

{triangledown} Published ahead of print on 19 November 2008.

Journal of Virology, February 2009, p. 1193-1200, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01023-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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