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Journal of Virology, February 2008, p. 1870-1883, Vol. 82, No. 4
0022-538X/08/$08.00+0     doi:10.1128/JVI.02228-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Chronic CD4+ T-Cell Activation and Depletion in Human Immunodeficiency Virus Type 1 Infection: Type I Interferon-Mediated Disruption of T-Cell Dynamics{triangledown}

Ahmad R. Sedaghat,1 Jennifer German,1,{dagger} Tanya M. Teslovich,2,{dagger} Joseph Cofrancesco Jr.,1 Chunfa C. Jie,2 C. Conover Talbot Jr.,2 and Robert F. Siliciano1,3*

Department of Medicine,1 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205,2 Howard Hughes Medical Institute, Baltimore Maryland 212053

Received 14 October 2007/ Accepted 27 November 2007

The mechanism of CD4+ T-cell depletion during chronic human immunodeficiency virus type 1 (HIV-1) infection remains unknown. Many studies suggest a significant role for chronic CD4+ T-cell activation. We assumed that the pathogenic process of excessive CD4+ T-cell activation would be reflected in the transcriptional profiles of activated CD4+ T cells. Here we demonstrate that the transcriptional programs of in vivo-activated CD4+ T cells from untreated HIV-positive (HIV+) individuals are clearly different from those of activated CD4+ T cells from HIV-negative (HIV–) individuals. We observed a dramatic up-regulation of cell cycle-associated and interferon-stimulated transcripts in activated CD4+ T cells of untreated HIV+ individuals. Furthermore, we find an enrichment of proliferative and type I interferon-responsive transcription factor binding sites in the promoters of genes that are differentially expressed in activated CD4+ T cells of untreated HIV+ individuals compared to those of HIV– individuals. We confirm these findings by examination of in vivo-activated CD4+ T cells. Taken together, these results suggest that activated CD4+ T cells from untreated HIV+ individuals are in a hyperproliferative state that is modulated by type I interferons. From these results, we propose a new model for CD4+ T-cell depletion during chronic HIV-1 infection.

* Corresponding author. Mailing address: Johns Hopkins University School of Medicine, Department of Medicine, 879 BRB, 733 N. Broadway, Baltimore, Maryland 21205. Phone: (410) 955-2958. Fax: (443) 287-6218. E-mail: rsiliciano{at}jhmi.edu

{triangledown} Published ahead of print on 12 December 2007.

{dagger} J.G. and T.M.T. contributed equally.

Journal of Virology, February 2008, p. 1870-1883, Vol. 82, No. 4
0022-538X/08/$08.00+0     doi:10.1128/JVI.02228-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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