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Metabolic pathway activation distinguishes transcriptional signatures of CD8+ T cells from HIV-1 elite controllers

Chowdhury, Fatema Z.a; Ouyang, Zhengyua; Buzon, Mariaa; Walker, Bruce D.a,b; Lichterfeld, Mathiasa,c; Yu, Xu G.a,c

doi: 10.1097/QAD.0000000000002007
BASIC SCIENCE

Objective: Elite controllers, defined as persons maintaining undetectable levels of HIV-1 replication in the absence of antiretroviral therapy, represent living evidence that sustained, natural control of HIV-1 is possible, at least in relatively rare instances. Understanding the complex immunologic and virologic characteristics of these specific patients holds promise for inducing drug-free control of HIV-1 in broader populations of HIV-1 infected patients.

Design: We used an unbiased transcriptional profiling approach to characterize CD8+ T cells, the strongest correlate of HIV-1 immune control identified thus far, in a large cohort of elite controllers (n = 51); highly active antiretrovial therapy (HAART)-treated patients (n = 32) and HIV-1 negative (n = 10) served as reference cohorts.

Methods: We isolated mRNA from total CD8+ T cells isolated from peripheral blood mononuclear cell (PBMC) of each individual followed by microarray analysis of the transcriptional signatures.

Results: We observed profound transcriptional differences [590 transcripts, false discovery rate (FDR)-adjusted P < 0.05] between elite controller and HAART-treated patients. Interestingly, metabolic and signalling pathways governed by mammalian target of rapamycin (mTOR) and eIF2, known for their key roles in regulating cellular growth, proliferation and metabolism, were among the top functions enriched in the differentially expressed genes, suggesting a therapeutically actionable target as a distinguishing feature of spontaneous HIV-1 immune control. A subsequent bootstrapping approach distinguished five different subgroups of elite controller, each characterized by distinct transcriptional signatures. However, despite this marked heterogeneity, differential regulation of mTOR and eIF2 signalling remained the dominant functional pathway in three of these elite controller subgroups.

Conclusion: These studies suggest that mTOR and eIF2 signalling may play a remarkably universal role for regulating CD8+ T-cell function from elite controllers.

aRagon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Cambridge, Massachusetts

bHoward Hughes Medical Institute, Chevy Chase, Maryland

cDivision of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Correspondence to Xu G. Yu, MD, MSc, Associate Professor of Medicine, Ragon Institute of MGH, MIT and Harvard, 400 Technology Square, Cambridge, MA 02139, USA. Tel: +1 857 268 7004; e-mail: XYU@mgh.harvard.edu

Received 16 April, 2018

Accepted 19 June, 2018

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Copyright © 2018 Wolters Kluwer Health, Inc.