Abstract
BackgroundHuman 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.ResultsTo 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.ConclusionsOverall, 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.
Highlights
Human immunity relies on the coordinated responses of many cellular subsets and functional states
Shared elite controllers (ECs) myeloid dendritic cells (mDCs) subsets revealed by scRNA-seq In order to identify features of mDC (CD14, CD11cHi, HLA-DR+) innate immune responses to HIV-1 shared across ECs, we performed scRNA-seq [2, 9, 10, 26, 27] on peripheral blood mononuclear cells (PBMCs) from three ECs (p1, p2, p3) exposed in vitro to either a VSVG pseudotyped HIV-1 virus or a media control for 48 h (Fig. 1a, see “Methods”) [28]
Stimulating PBMCs mimics some of the critical physiological interactions that occur between mDCs and other immune cell types, while the use of a vesicular stomatitis virus G envelop (VSV-G) pseudotyped HIV-1 particles enhances mDC infection efficiency [29]
Summary
Human immunity relies on the coordinated responses of many cellular subsets and functional states. Studies of elite controllers (ECs)—a rare (~ 0.5%) subset of HIV-1 infected individuals who naturally suppress viral replication without combination antiretroviral therapy (cART) [15, 16]—have highlighted the importance of specific HLA-B variants and enhanced cytotoxic CD8+ T cell responses [17, 18]. Compelling, these findings have proven insufficient to explain the frequency of viral control in the general population; additional cellular components or interactions could be implicated in coordinating effective host defense. The master regulators driving this mDC functional state, the fraction of EC mDCs that assume it, its biomarkers, and how to potentially enrich for it are unknown
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