Herbeuval Jean-Philippe, Nilsson Jakob, Boasso Adriano, Hardy Andrew W, Kruhlak Michael J, Anderson Stephanie A, Dolan Matthew J, Dy Michel, Andersson Jan, Shearer Gene M
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20092, USA.
Proc Natl Acad Sci U S A. 2006 May 2;103(18):7000-5. doi: 10.1073/pnas.0600363103. Epub 2006 Apr 21.
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.
CD4+ T细胞的丧失是HIV发病机制的标志，据认为部分是由于细胞凋亡所致。我们最近报道，HIV-1激活的浆细胞样树突状细胞（pDCs）产生的IFN-α通过肿瘤坏死因子相关凋亡诱导配体（TRAIL）/死亡受体（DR）5途径促成CD4+ T细胞凋亡。在此，我们表明，HIV-1在体内和体外诱导pDCs中IFN-α的细胞内表达与pDCs中IFN调节因子7和MyD88表达的增加相关联。与非进展性（HIV(NP)）HIV-1疾病患者及未感染对照相比，进展性（HIV(prog)）患者的淋巴样扁桃体组织（LT）中IFN-α的表达增加。HIV(prog)患者的LT中TRAIL和DR5 mRNA水平高于HIV(NP)患者或对照的LT。LT中的TRAIL mRNA水平与血浆病毒载量相关。我们表明，HIV-1在LT中诱导IFN-α及TRAIL/DR5凋亡途径，提示这些细胞因子在HIV-1免疫发病机制中发挥作用。
