DNA methylation changes in metabolic and immune-regulatory pathways in blood and lymph node CD4\u2009+\u2009T cells in response to SIV infections

Simon P Jochems,Roger Le Grand,Elodie Roché,Fabien Pichon,Beatrice Jacquelin,Nathalie Dereuddre-Bosquet,Rémi Cheynier,Florence Busato,Jorg Tost,Mickaël J Ploquin,Michaela Müller-Trutwin,Nicolas Tchitchek,Nicolas Huot,Christiane Stahl-Henning,Yi Liu

doi:10.1186/s13148-020-00971-w

Abstract

The molecular mechanisms underlying HIV-induced inflammation, which persists even during effective long-term treatment, remain incompletely defined. Here, we studied pathogenic and nonpathogenic simian immunodeficiency virus (SIV) infections in macaques and African green monkeys, respectively. We longitudinally analyzed genome-wide DNA methylation changes in CD4 + T cells from lymph node and blood, using arrays. DNA methylation changes after SIV infection were more pronounced in lymph nodes than blood and already detected in primary infection. Differentially methylated genes in pathogenic SIV infection were enriched for Th1-signaling (e.g., RUNX3, STAT4, NFKB1) and metabolic pathways (e.g., PRKCZ). In contrast, nonpathogenic SIVagm infection induced DNA methylation in genes coding for regulatory proteins such as LAG-3, arginase-2, interleukin-21 and interleukin-31. Between 15 and 18% of genes with DNA methylation changes were differentially expressed in CD4 + T cells in vivo. Selected identified sites were validated using bisulfite pyrosequencing in an independent cohort of uninfected, viremic and SIV controller macaques. Altered DNA methylation was confirmed in blood and lymph node CD4 + T cells in viremic macaques but was notably absent from SIV controller macaques. Our study identified key genes differentially methylated already in primary infection and in tissues that could contribute to the persisting metabolic disorders and inflammation in HIV-infected individuals despite effective treatment.

Highlights

DNA methylation, in concert with other epigenetic mechanisms, has multifaceted effects on the immune system, including T helper lineage fate determination [1], differentiation of memory cells [2], resolution of inflammation [3] and control of cellular proliferation [4]
simian immunodeficiency virus (SIV) infections course Five African green monkeys (AGM) and five Chinese rhesus MAC were infected with SIVagm.sab92018 and SIVmac251, respectively, and followed longitudinally (Additional file 2: Table 1)
For AGM lymph nodes (LN) CD4 + T cells, we identified 143 differentially methylated probes (DMP, 79 hypermethylated and 64 hypomethylated) during the acute phase and 521 Differentially methylated probes (DMP) (203 hypermethylated and 318 hypomethylated) during the chronic phase of SIV infection when compared to baseline (Fig. 1c, e)

Summary

Introduction

DNA methylation, in concert with other epigenetic mechanisms, has multifaceted effects on the immune system, including T helper lineage fate determination [1], differentiation of memory cells [2], resolution of inflammation [3] and control of cellular proliferation [4]. HIV and SIV infections in humans and macaques (MAC), respectively, induce a chronic state of immune activation, which is the driving force behind CD4 + T cell depletion and AIDS [8]. Under efficient anti-retroviral treatment (ART), residual inflammation persists in most individuals, increasing the risk of non-AIDS comorbidity and mortality [9]. Jochems et al Clin Epigenet (2020) 12:188 mechanisms underlying the persistent inflammation in virologically suppressed people living with HIV (PLWH) remain incompletely characterized [10]. HIV persists in cellular and anatomical reservoirs in virologically suppressed PLWH. Recent studies have elucidated that HIV targets preferentially CD4 + T cells that display a particular metabolic profile with strong glycolytic activity [11, 12]

Methods

Results

Conclusion