Differential expression of IFN-alpha and TRAIL/DR5 in lymphoid tissue of progressor versus nonprogressor HIV-1-infected patients.
Loss of CD4+ T cells, the hallmark of HIV pathogenesis, was suggested to be partly due to apoptosis. We recently reported that IFN-alpha produced by HIV-1-activated plasmacytoid dendritic cells (pDCs) contributes to CD4+ T cell apoptosis by the TNF-related apoptosis-inducing ligand (TRAIL)/death receptor (DR)5 pathway. Here, we show that HIV-1-induced intracellular expression of IFN-alpha in pDCs is coupled to increased expression of IFN regulatory factor 7 and MyD88 by pDCs in vivo and in vitro. Expression of IFN-alpha was increased in lymphoid tonsillar tissue (LT) of patients with progressive (HIV(prog)) compared with nonprogressive (HIV(NP)) HIV-1 disease and to uninfected controls. LT from HIV(prog) exhibited higher TRAIL and DR5 mRNA levels than LT from HIV(NP) or controls. TRAIL mRNA levels in LT correlated with plasma viral load. We show that HIV-1 induces IFN-alpha and the TRAIL/DR5 apoptotic pathway in LT, suggesting a role for these cytokines in HIV-1 immunopathogenesis.
Herbeuval
Jean-Philippe
JP
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20092, USA.
Nilsson
Jakob
J
Boasso
Adriano
A
Hardy
Andrew W
AW
Kruhlak
Michael J
MJ
Anderson
Stephanie A
SA
Dolan
Matthew J
MJ
Dy
Michel
M
Andersson
Jan
J
Shearer
Gene M
GM
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology; D000328:Adult; D017209:Apoptosis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000276:immunology / Q000473:pathology; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000276:immunology; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008297:Male; D053594:Myeloid Differentiation Factor 88; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D014775:Virus Activation; D019014:fas Receptor / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C505639:TNFRSF10B protein, human; D019014:fas Receptor