Dataset Information

Contribution of intestinal barrier damage, microbial translocation and HIV-1 infection status to an inflammaging signature.

ABSTRACT:

Background

Systemic inflammation is a characteristic of both HIV-1 infection and aging ("inflammaging"). Intestinal epithelial barrier damage (IEBD) and microbial translocation (MT) contribute to HIV-associated inflammation, but their impact on inflammaging remains unclear.

Methods

Plasma biomarkers for IEBD (iFABP), MT (LPS, sCD14), T-cell activation (sCD27), and inflammation (hsCRP, IL-6) were measured in 88 HIV-1 uninfected (HIV(neg)) and 83 treated, HIV-1-infected (HIV(pos)) adults from 20-100 years old.

Results

Age positively correlated with iFABP (r = 0.284, p = 0.008), sCD14 (r = 0.646, p =?<0.0001) and LPS (r = 0.421, p = 0.0002) levels in HIV(neg) but not HIV(pos) subjects. Age also correlated with sCD27, hsCRP, and IL-6 levels regardless of HIV status. Middle-aged HIV(pos) subjects had elevated plasma biomarker levels similar to or greater than those of elderly HIV(neg) subjects with the exception of sCD14. Clustering analysis described an inflammaging phenotype (IP) based on iFABP, sCD14, sCD27, and hsCRP levels in HIV(neg) subjects over 60 years of age. The IP in HIV(neg) subjects was used to develop a classification model that was applied to HIV(pos) subjects to determine whether HIV(pos) subjects under 60 years of age were IP+. HIV(pos) IP+ subjects were similar in age to IP- subjects but had a greater risk of cardiovascular disease (CVD) based on Framingham risk score (p =? 0.01).

Conclusions

We describe a novel IP that incorporates biomarkers of IEBD, MT, immune activation as well as inflammation. Application of this novel IP in HIV-infected subjects identified a group at higher risk of CVD.

SUBMITTER: Steele AK

PROVIDER: S-EPMC4018269 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Contribution of intestinal barrier damage, microbial translocation and HIV-1 infection status to an inflammaging signature.

Steele Amanda K AK Lee Eric J EJ Vestal Brian B Hecht Daniel D Dong Zachary Z Rapaport Eric E Koeppe John J Campbell Thomas B TB Wilson Cara C CC

PloS one 20140512 5

<h4>Background</h4>Systemic inflammation is a characteristic of both HIV-1 infection and aging ("inflammaging"). Intestinal epithelial barrier damage (IEBD) and microbial translocation (MT) contribute to HIV-associated inflammation, but their impact on inflammaging remains unclear.<h4>Methods</h4>Plasma biomarkers for IEBD (iFABP), MT (LPS, sCD14), T-cell activation (sCD27), and inflammation (hsCRP, IL-6) were measured in 88 HIV-1 uninfected (HIV(neg)) and 83 treated, HIV-1-infected (HIV(pos)) a ...[more]

PMID: 24819230

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Project description:BackgroundDespite effective antiretroviral therapy (ART), patients with chronic human immunodeficiency virus (HIV) infection have increased microbial translocation and systemic inflammation. Alterations in the intestinal microbiota may play a role in microbial translocation and inflammation.MethodsWe profiled the fecal microbiota by pyrosequencing the gene encoding 16S ribosomal RNA (rRNA) and measured markers of microbial translocation and systemic inflammation in 21 patients who had chronic HIV infection and were receiving suppressive ART (cases) and 16 HIV-uninfected controls.ResultsThe fecal microbial community composition was significantly different between cases and controls. The relative abundance of Proteobacteria, Gammaproteobacteria, Enterobacteriales, Enterobacteriaceae, Erysipelotrichi, Erysipelotrichales, Erysipelotrichaceae, and Barnesiella was significantly enriched in cases, whereas that of Rikenellaceae and Alistipes was depleted. The plasma soluble CD14 level (sCD14) was significantly higher and the endotoxin core immunoglobulin M (IgM) level lower in cases, compared with controls. There were significant positive correlations between the relative abundances of Enterobacteriales and Enterobacteriaceae and the sCD14 level; the relative abundances of Gammaproteobacteria, Enterobacteriales, and Enterobacteriaceae and the interleukin 1β (IL-1β) level; the relative abundances of Enterobacteriales and Enterobacteriaceae and the interferon γ level; and the relative abundances of Erysipelotrichi and Barnesiella and the TNF-α level. There were negative correlations between endotoxin core IgM and IL-1β levels.ConclusionsPatients who have chronic HIV infection and are receiving suppressive ART display intestinal dysbiosis associated with increased microbial translocation and significant associations between specific taxa and markers of microbial translocation and systemic inflammation. This was an exploratory study, the findings of which need to be confirmed.

Project description:While several clinical studies have shown that HIV-1 infection is associated with increased permeability of the intestinal tract, there is very little understanding of the mechanisms underlying HIV-induced impairment of mucosal barriers. Here we demonstrate that exposure to HIV-1 can directly breach the integrity of mucosal epithelial barrier, allowing translocation of virus and bacteria. Purified primary epithelial cells (EC) isolated from female genital tract and T84 intestinal cell line were grown to form polarized, confluent monolayers and exposed to HIV-1. HIV-1 X4 and R5 tropic laboratory strains and clinical isolates were seen to reduce transepithelial resistance (TER), a measure of monolayer integrity, by 30-60% following exposure for 24 hours, without affecting viability of cells. The decrease in TER correlated with disruption of tight junction proteins (claudin 1, 2, 4, occludin and ZO-1) and increased permeability. Treatment of ECs with HIV envelope protein gp120, but not HIV tat, also resulted in impairment of barrier function. Neutralization of gp120 significantly abrogated the effect of HIV. No changes to the barrier function were observed when ECs were exposed to Env defective mutant of HIV. Significant upregulation of inflammatory cytokines, including TNF-alpha, were seen in both intestinal and genital epithelial cells following exposure to HIV-1. Neutralization of TNF-alpha reversed the reduction in TERs. The disruption in barrier functions was associated with viral and bacterial translocation across the epithelial monolayers. Collectively, our data shows that mucosal epithelial cells respond directly to envelope glycoprotein of HIV-1 by upregulating inflammatory cytokines that lead to impairment of barrier functions. The increased permeability could be responsible for small but significant crossing of mucosal epithelium by virus and bacteria present in the lumen of mucosa. This mechanism could be particularly relevant to mucosal transmission of HIV-1 as well as immune activation seen in HIV-1 infected individuals.

Dataset Information

Contribution of intestinal barrier damage, microbial translocation and HIV-1 infection status to an inflammaging signature.

Background

Methods

Results

Conclusions

Publications

Contribution of intestinal barrier damage, microbial translocation and HIV-1 infection status to an inflammaging signature.

Similar Datasets

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