A Reproducibility-Based Computational Framework Identifies an Inducible, Enhanced Antiviral State in Dendritic Cells from HIV-1 Elite Controllers

Genome Biology. 2018;19(1):1-21 DOI 10.1186/s13059-017-1385-x

 

Journal Homepage

Journal Title: Genome Biology

ISSN: 1474-760X (Online)

Publisher: BMC

LCC Subject Category: Science: Biology (General): Genetics

Country of publisher: United Kingdom

Language of fulltext: English

Full-text formats available: PDF, HTML

 

AUTHORS

Enrique Martin-Gayo (Ragon Institute of MGH, MIT and Harvard)
Michael B. Cole (Department of Physics, University of California)
Kellie E. Kolb (Ragon Institute of MGH, MIT and Harvard)
Zhengyu Ouyang (Ragon Institute of MGH, MIT and Harvard)
Jacqueline Cronin (Ragon Institute of MGH, MIT and Harvard)
Samuel W. Kazer (Ragon Institute of MGH, MIT and Harvard)
Jose Ordovas-Montanes (Ragon Institute of MGH, MIT and Harvard)
Mathias Lichterfeld (Ragon Institute of MGH, MIT and Harvard)
Bruce D. Walker (Ragon Institute of MGH, MIT and Harvard)
Nir Yosef (Ragon Institute of MGH, MIT and Harvard)
Alex K. Shalek (Ragon Institute of MGH, MIT and Harvard)
Xu G. Yu (Ragon Institute of MGH, MIT and Harvard)

EDITORIAL INFORMATION

Blind peer review

Editorial Board

Instructions for authors

Time From Submission to Publication: 14 weeks

 

Abstract | Full Text

Abstract Background Human immunity relies on the coordinated responses of many cellular subsets and functional states. Inter-individual variations in cellular composition and communication could thus potentially alter host protection. Here, we explore this hypothesis by applying single-cell RNA-sequencing to examine viral responses among the dendritic cells (DCs) of three elite controllers (ECs) of HIV-1 infection. Results To overcome the potentially confounding effects of donor-to-donor variability, we present a generally applicable computational framework for identifying reproducible patterns in gene expression across donors who share a unifying classification. Applying it, we discover a highly functional antiviral DC state in ECs whose fractional abundance after in vitro exposure to HIV-1 correlates with higher CD4+ T cell counts and lower HIV-1 viral loads, and that effectively primes polyfunctional T cell responses in vitro. By integrating information from existing genomic databases into our reproducibility-based analysis, we identify and validate select immunomodulators that increase the fractional abundance of this state in primary peripheral blood mononuclear cells from healthy individuals in vitro. Conclusions Overall, our results demonstrate how single-cell approaches can reveal previously unappreciated, yet important, immune behaviors and empower rational frameworks for modulating systems-level immune responses that may prove therapeutically and prophylactically useful.