Focused Examination of the Intestinal lamina Propria Yields Greater Molecular Insight into Mechanisms Underlying SIV Induced Immune Dysfunction

Mahesh Mohan,Xavier Alvarez,Andrew A Lackner,Deepak Kaushal,Pyone P Aye,Ronald S Veazey,Jan-Hendrik Niess

doi:10.1371/journal.pone.0034561

Abstract

BackgroundThe Gastrointestinal (GI) tract is critical to AIDS pathogenesis as it is the primary site for viral transmission and a major site of viral replication and CD4+ T cell destruction. Consequently GI disease, a major complication of HIV/SIV infection can facilitate translocation of lumenal bacterial products causing localized/systemic immune activation leading to AIDS progression.Methodology/Principal FindingsTo better understand the molecular mechanisms underlying GI disease we analyzed global gene expression profiles sequentially in the intestine of the same animals prior to and at 21 and 90d post SIV infection (PI). More importantly we maximized information gathering by examining distinct mucosal components (intraepithelial lymphocytes, lamina propria leukocytes [LPL], epithelium and fibrovascular stroma) separately. The use of sequential intestinal resections combined with focused examination of distinct mucosal compartments represents novel approaches not previously attempted. Here we report data pertaining to the LPL. A significant increase (±1.7-fold) in immune defense/inflammation, cell adhesion/migration, cell signaling, transcription and cell division/differentiation genes were observed at 21 and 90d PI. Genes associated with the JAK-STAT pathway (IL21, IL12R, STAT5A, IL10, SOCS1) and T-cell activation (NFATc1, CDK6, Gelsolin, Moesin) were notably upregulated at 21d PI. Markedly downregulated genes at 21d PI included IL17D/IL27 and IL28B/IFNγ3 (anti-HIV/viral), activation induced cytidine deaminase (B-cell function) and approximately 57 genes regulating oxidative phosphorylation, a critical metabolic shift associated with T-cell activation. The 90d transcriptome revealed further augmentation of inflammation (CXCL11, chitinase-1, JNK3), immune activation (CD38, semaphorin7A, CD109), B-cell dysfunction (CD70), intestinal microbial translocation (Lipopolysaccharide binding protein) and mitochondrial antiviral signaling (NLRX1) genes. Reduced expression of CD28, CD4, CD86, CD93, NFATc1 (T-cells), TLR8, IL8, CCL18, DECTIN1 (macrophages), HLA-DOA and GPR183 (B-cells) at 90d PI suggests further deterioration of overall immune function.Conclusions/SignificanceThe reported transcriptional signatures provide significant new details on the molecular pathology of HIV/SIV induced GI disease and provide new opportunity for future investigation.

Highlights

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are characterized by continuous CD4+ T cell destruction, chronic immune activation and increased susceptibility to opportunistic infections that are controlled by healthy individuals [1]
The time points chosen were selected as they represent the nadir of CD4+ T cell depletion and establishment of viral set point. Using this novel combinatorial approach we have identified unique transcriptional signatures related to key pathogenic events such as immune activation, inflammation, epithelial barrier disruption, immune cell dysfunction and mitochondrial anti-viral signaling in intestinal lamina propria leukocytes (LPLs) at 21 and 90 d post SIV infection (PI)
Intestinal homeostasis is drastically altered during HIV/SIV infection as a result of massive loss of mucosal CD4+ T cells which leads to structural and functional damage [7,8,9]

Summary

Introduction

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are characterized by continuous CD4+ T cell destruction, chronic immune activation and increased susceptibility to opportunistic infections that are controlled by healthy individuals [1]. The gastrointestinal immune system, in particular, is an important target of HIV/SIV as it is the largest immunologic organ and a major site for viral replication and CD4+ T cell destruction (as early as 21 days post infection) [2,3,4,5,6]. Breakdown of the intestinal epithelial cell barrier, a common occurrence in intestinal disease, was shown to facilitate translocation of intestinal lumenal bacteria and their products into the systemic circulation leading to chronic activation of the immune system and progression to AIDS [10]. GI disease, a major complication of HIV/SIV infection can facilitate translocation of lumenal bacterial products causing localized/systemic immune activation leading to AIDS progression

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Conclusion