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Platelet Transcriptome Profiling in HIV and ABCC4 as a Biomarker of Platelet Activity

ABSTRACT: The purpose of this study was to perform an unbiased RNA expression profile in platelets from HIV subjects under ART and healthy controls to identify a gene signature for the HIV hyperactive phenotype. Methods: Rna-Sequencing was performed in leukocyte-depleted platelet RNA from 6 HIV subjects and 3 healthy controls. qRT–PCR validation was performed to validate our candidate transcripts. Results: Across the 9 platelet samples, there was an average of 28.3 million mapped reads per sample with an average unique mapping rate of 91.6 %. Using a cut-off of normalized counts ≥1 across the 9 samples, we found 11988 expressed transcripts. Conclusions: Our study represents a detailed analysis of platelet transcriptome generated by RNA-seq technology in HIV patients under ART. Further experiments identified the mechanism of our transcript target in mediating platelet activity and platelet cell effector function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE99737 | GEO | 2018/06/10

REPOSITORIES: GEO

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Project description:Background. HIV-infected individuals on antiretroviral therapy (HIV/ART) experience higher levels of non-AIDS morbidity than uninfected people, which is believed to be driven by inflammation that persists despite viral suppression. Elevations in plasma cytokines, coagulation markers and both innate and adaptive immune cell activation during untreated infection are often incompletely reversed by ART and associated with these morbidities. Monocytes/macrophages play a central role in many of these complications including neurocognitive and cardiovascular disease. Results. We investigated monocyte surface markers, gene expression and plasma cytokines in 11 HIV-infected older individuals (median age 53 years) who started therapy with low CD4 counts (median 129 cells/ul), with elevated hsCRP (≥2mg/L) despite long-term ART (median 7.4 years), along with age, gender, race and smoking status-matched controls. Major monocyte subsets (based on CD14/CD16/CD163) were not different from controls, but surface levels differed for CD163 (p=0.022), PD1 (p=0.015) and a trend for tissue factor (p=0.098). As a group, HIV/ART subjects had elevated levels of plasma CCL2 (MCP-1; p=0.0001), CXCL9 (MIG; p=0.04) and sIL2R (p=0.015), which were highly correlated, whereas sCD14 and several other markers were not significantly elevated. However, principal component analysis of soluble markers revealed that about half of HIV/ART subjects clustered with controls, whereas the remainder were distinct, driven by IL-10, CCL11, CXCL10, CXCL11 as well as CCL2, CXCL9 and sIL2R. Outlier subjects were significantly older than those who clustered with controls. Gene expression analysis unexpectedly revealed downregulation in HIV/ART monocytes of multiple genes linked to immune functions including inflammation, immune cell development and cell-cell signaling. Conclusions. These results reveal a novel pattern of immune dysregulation involving both aberrant inflammation and monocyte dysfunction, which suggests complex mechanisms linking monocytes and HIV/ART comorbidities.

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Platelet Transcriptome Profiling in HIV and ABCC4 as a Biomarker of Platelet Activity

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