constitutive gene expression in monocytes from chronic hiv-1 infection overlaps with acute toll-like receptor induced monocyte activation profiles本构基因表达在单核细胞从慢性hiv - 1感染与急性toll样受体诱导单核细胞激活配置文件.pdf

Constitutive Gene Expression in Monocytes from Chronic HIV-1 Infection Overlaps with Acute Toll-Like Receptor Induced Monocyte Activation Profiles 1 1 1 1 1 Bethsebah Gekonge , Malavika S. Giri , Andrew V. Kossenkov , Michael Nebozyhn , Malik Yousef , 2 1 1 Karam Mounzer , Louise Showe , Luis J. Montaner * 1The Wistar Institute, Philadelphia, Pennsylvania, United States of America, 2 Philadelphia Field Initiating Group for HIV-1 Trials, Philadelphia, Pennsylvania, United States of America Abstract Elevated TLR expression/signalling in monocyte/macrophages has been shown to mediate systemic immune activation, a hallmark of progressive HIV-1 infection. Here we show, via differential gene expression comparisons, the presence of a constitutive in vivo TLR-like gene activation signature in steady-state circulating monocytes from chronically HIV-1 infected subjects. The TLR2-like gene signature was defined as an 82 gene subset of the 376 genes constitutively modulated in in vivo HIV-1 monocytes, based on their overlap with de novo TLR2-induced genes in uninfected subjects’ monocytes following acute ex vivo stimulation with Staphylococcus Aureus Cowan (SAC). Additional comparison of in vivo gene networks with available datasets from acute TLR activations in M/M expanded the overlap to 151-gene concordance among the 376 differential genes with emphasis on ERK/MAPK, TNF/IL6 (NFkB) and p53 gene networks. TLR2 stimulation of monocytes from HIV-1 infected subjects resulted in further upregulation of inflammatory genes indicative of a sustained transcriptional potential upon stimulation. In summary, our data support the presence of a su