Chronic CD4+ T-cell activation and depletion in human immunodeficiency virus type 1 infection: type I interferon-mediated disruption of T-cell dynamics.
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.
Sedaghat
Ahmad R
AR
Johns Hopkins University School of Medicine, Department of Medicine, 879 BRB, 733 N. Broadway, Baltimore, Maryland 21205, USA.
German
Jennifer
J
Teslovich
Tanya M
TM
Cofrancesco
Joseph
J
Jie
Chunfa C
CC
Talbot
C Conover
CC
Siliciano
Robert F
RF
D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002453:Cell Cycle / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics*; D008212:Lymphocyte Depletion; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; D007370:Interferon Type I