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HIV Stimulation Induces a Unique Innate Immune Response in Kupffer Cells

ABSTRACT: BACKGROUND: Patients with HIV that are coinfected with HCV are at increased risk for rapidly progressive liver disease and subsequently the development of Hepatocellular Carcinoma (HCC). Specifically, HCC develops earlier in coinfected patients and these patients are more symptomatic than those with only HCV infection at diagnosis suggesting that both viruses increase the propensity for malignant transformation. Consequently, HCV coinfection and the associated liver disease is a major health burden for HIV infected persons in the U.S. However, the genetic and cellular based mechanisms underpinning how HCV initiates and subsequently induces liver pathology and why coinfection with HIV results in significantly worse hepatic disease remains to be clarified. In addition, the specific cell types that contribute to these clinical outcomes are unknown. METHODS: The goal of this project is focused on understanding the molecular mechanisms underlying the hepatic sequela in coinfected patients specifically focusing on the innate inflammatory responses activated by HIV in liver cells. To this end, we have developed novel in-vitro models that utilize HIV stimulated primary kupffer cells (PKCs). RESULTS: HIV stimulation of primary kupffer cells resulted in rapid and robust upregulation of an inflammatory gene signature. The goal of this study is to characterize the changes in gene expression triggered by HIV in primary human kupffer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE69589 | GEO | 2018/10/26

REPOSITORIES: GEO

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Project description:Chronic immune activation is a hallmark of human immunodeficiency virus (HIV) infection and the best prognostic indicator of disease progression. Suppressing HIV viremia by antiretroviral therapy (ART) restores normal immune response and effectively prolongs life. In HIV-infected individuals who are coinfected with hepatitis C virus (HCV) the immune system is activated despite effective HIV antiretroviral therapy controlling viral load. Here we examined CD14+ monocyte gene expression by high-density microarray analysis and T cell subsets, CD4 and CD8, by flow cytometry to characterize immune activation in monoinfected HCV, monoinfected HIV and HIV/HCV coinfected subjects with undetected HIV viral load. To determine the impact of coinfection on cognition, subjects were evaluated in 7 domains for neuropsychological (NP) performance, which was summarized as global deficit scores (GDS). Gene expression analysis of CD14+ monocytes from coinfected subjects revealed an elevated type 1 interferon (IFN) response profile unique to coinfection. For both CD4 and CD8 T cells, coinfection triggered significantly increased expression of activation markers CD38 and HLA-DR. In the coinfected group, mild cognitive impairment was associated with a type 1 IFN monocyte response but not plasma lipopolysaccharide. These observations raise the possibility that cognitive impairment evident in the HIV/HCV population is associated with the IFN response detected in coinfected individuals. Monocytes isolated from healthy controls (n=17), HCV monoinfected (n=19) and HIV/HCV coinfected (n=17) were analyzed for gene expression using high-density microarrays. Whole blood was collected in Vacutainer CPT tubes (BD Biosciences) and PBMCs were enriched by centrifugation. Typically, three million CD14+ monocytes were isolated from 30 ml of whole blood using an anti-CD14 monoclonal antibody immunomagnetic - ferrous bead conjugate according to the manufacturer’s instructions (Miltenyi Biotech). Monocyte purity exceeded 97% with <1% T or B cell contamination as determined by flow cytometry. Monocyte RNA was isolated using a Qiagen RNeasy Micro Kit with an RNA integrity value exceeding 9. Complementary DNA was synthesized and labeled with biotin (iExpress iAmplify kit, Applied Microarrays) and hybridized to Codelink Whole Human Genome Bioarrays (55K probes, Applied Microarrays). Slides were scanned (Axon GenePix 4000B, Molecular Devices), analyzed (CodeLink Expression Software Kit v4.1) and microarray data were normalized with loess normalization using R and Bioconductor package. Determination of differential gene expression and multiple testing correction / false discovery rate adjustments were performed using GeneSpring GX 7.3 software package (Agilent). Microarray data was analyzed using a variety of custom data analytic techniques for gene expression profile identification as described previously. Correlations were determined by Spearman rank correlation coefficient.

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HIV Stimulation Induces a Unique Innate Immune Response in Kupffer Cells

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