Genome-wide analysis of primary peripheral blood mononuclear cells from HIV + patients-pre-and post- HAART show immune activation and inflammation the main drivers of host gene expression.

Viviane N Da Conceicao,Priyanka Gupta,Nitin K Saksena,Kaushal Gandhi,Wayne B Dyer

doi:10.1186/2052-8426-2-11

Abstract

BackgroundAlthough the host gene expression in the context of HIV has been explored by several studies, it remains unclear how HIV is able to manipulate and subvert host gene machinery before and after highly active antiretroviral therapy (HAART) in the same individual. In order to define the underlying pharmaco-genomic basis of HIV control during HAART and genomic basis of immune deterioration prior to HAART initiation, we performed a genome-wide expression analysis using primary peripheral blood mononuclear cells (PBMC) derived from 14 HIV + subjects pre-highly active antiretroviral therapy (HAART) (time point-1 or TP1) with detectable plasma viremia and post-HAART (time point-2 or TP2) with effective control of plasma viremia (<40 HIV RNA copies/mL of plasma).MethodsGenomic RNA extracted from the PBMCs was used in microarray analysis using HT-12V3 Illumina chips. Illumina®BeadStudio Software was used to obtain differentially expressed (DE) genes. Only the genes with p value <0.01 and FDR of <5% were considered for analysis. Pathway analysis was performed in MetaCore™ to derive functional annotations. Functionally significant genes were validated by qRT-PCR.ResultsBetween TP1 and TP2, 234 genes were differentially expressed (DE). During viremic phase (TP1), there was an orchestrated and coordinated up-regulation of immune, inflammation and antiviral genes, consistent with HIV infection and immune activation, which comprised of genes mainly involved in antiviral action of interferons and their signalling. In contrast, the therapy-mediated control phase (TP2) showed systematic down-regulation of these pathways, suggesting that the reduction in plasma viremia with HAART has a considerable influence on reducing the immune activation, thereby implying a definitive role of HIV in subverting the human gene machinery.ConclusionsThis is the first study to show the evidence for the differential regulation of gene expression between the untreated and treated time points, suggesting that gene expression is a consequence of cellular activation during plasma viremia. Affirmation to these observations comes from down-modulation of genes involved in cellular activation and inflammation upon initiation of HAART coinciding with below detectable levels of plasma viremia.Electronic supplementary materialThe online version of this article (doi:10.1186/2052-8426-2-11) contains supplementary material, which is available to authorized users.

Highlights

The host gene expression in the context of HIV has been explored by several studies, it remains unclear how HIV is able to manipulate and subvert host gene machinery before and after highly active antiretroviral therapy (HAART) in the same individual
The natural history of HIV is tightly governed by the plasma viral load and T cell modulation in the absence of HAART, which results in massive destruction of CD4+ T cells by multiple mechanisms, leading to T cell exhaustion
We show for the first time a genome-wide snapshot of transcriptomic expression demonstrating that the up-regulation of genes involved in innate and adaptive immunity, inflammation, apoptosis and antiviral functions were unique to pretherapy with detectable plasma viremia, while their downregulation coincided with complete suppression of plasma virus to below detectable levels (

Summary

Introduction

The host gene expression in the context of HIV has been explored by several studies, it remains unclear how HIV is able to manipulate and subvert host gene machinery before and after highly active antiretroviral therapy (HAART) in the same individual. It is apparent that HIV targets CD4+ T cells, and has the ability to infect a variety of blood leukocytes [1,3,4,5] This shows that HIV has the inherent ability to subvert and manipulate the host gene machinery at the transcriptomic level [6,7,8], thereby having considerable influence on the cell morphology, gene expression, and metabolism. The global effects of viral infection on host cell gene expression patterns pre- and post- antiretroviral therapy in HIV + patients, still remain poorly understood [9]. The high-density genome-wide microarrays have greatly facilitated the understanding of genomic basis of host-pathogen and pharmaco-genomic interactions [9,10]

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Conclusion