The Impact of HIV Co-Infection on the Genomic Response to Sepsis.

Michaëla A M Huson,Mohammad R Toliat,Arie J Hoogendijk,Marc J M Bonten,Olaf L Cremer,Marek Franitza,Lonneke A Van Vught,Martin P Grobusch,Brendon P Scicluna,Marcus J Schultz,Tom Van Der Poll,Peter Nürnberg,Maryse A Wiewel,Aftab A Ansari

doi:10.1371/journal.pone.0148955

Abstract

HIV patients have an increased risk to develop sepsis and HIV infection affects several components of the immune system involved in sepsis pathogenesis. We hypothesized that HIV infection might aggrevate the aberrant immune response during sepsis, so we aimed to determine the impact of HIV infection on the genomic host response to sepsis. We compared whole blood leukocyte gene expression profiles among sepsis patients with or without HIV co-infection in the intensive care unit (ICU) and validated our findings in a cohort of patients admitted to the same ICUs in a different time frame. To examine the influence of HIV infection per se, we also determined the expression of genes of interest in a cohort of asymptomatic HIV patients. We identified a predominantly common host response in sepsis patients with or without HIV co-infection. HIV positive sepsis patients in both ICU cohorts showed overexpression of genes involved in granzyme signaling (GZMA, GZMB), cytotoxic T-cell signaling (CD8A, CD8B) and T-cell inhibitory signaling (LAG3), compared to HIV negative patients. Enhanced expression of CD8A, CD8B and LAG3 was also unmasked in asymptomatic HIV patients. Plasma levels of granzymes in sepsis patients were largely below detection limit, without differences according to HIV status. These results demonstrate that sepsis is characterized by a massive common response with few differences between HIV positive and HIV negative sepsis patients. Observed differences in granzyme signaling, cytotoxic T-cell signaling and T-cell inhibitory signaling appear to be changes commonly observed in asymptomatic HIV patients which persist during sepsis.

Highlights

Sepsis is a major cause of morbidity and mortality in patients with HIV
Whole genome transcriptome profiling of blood leukocytes was performed on 20 HIV patients admitted with sepsis, diagnosed within 24 hours after intensive care unit (ICU) admission, between January 2011 and July 2012, and 40 matched HIV negative patients admitted with sepsis during the same period
Gene transcripts differentially expressed in HIV positive and HIV negative patients in the first cohort were determined by reverse transcribed quantitative polymerase chain reaction in a second independent cohort derived from the same two ICUs, comprising 12 HIV positive and 24 matched HIV negative patients admitted with sepsis between July 2012 and January 2014

Summary

Introduction

Sepsis is a major cause of morbidity and mortality in patients with HIV. In Western settings, sepsis accounts for 33–35% of intensive care unit (ICU) admissions in HIV/AIDS patients, and is associated with high mortality [1, 2]. Two previous studies examined the cytokine response in sepsis patients with or without HIV co-infection and found few differences in cytokine levels [7, 8]. In Malawian children with bacterial sepsis, those with HIV co-infection had more profound increases in angiopoietin 2, an angiogenic peptide that increases endothelial activation and is associated with disseminated intravascular coagulation and mortality in sepsis [9]. We demonstrated an additive effect of HIV co-infection on complement activation during sepsis [10]. These studies suggest that HIV co-infection enhances essential aspects of the pro-inflammatory response during sepsis

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