Monocyte-derived transcriptome signature indicates antibody-dependent cellular phagocytosis as a potential mechanism of vaccine-induced protection against HIV-1
Abstract
A gene signature previously correlated with mosaic adenovirus 26 vaccine protection in simian immunodeficiency virus (SIV) and SHIV challenge models in non-human primates (NHP). In this report we investigated presence of this signature as a correlate of reduced risk in human clinical trials and potential mechanisms of protection. The absence of this gene signature in the DNA/rAd5 human vaccine trial, which did not show efficacy, strengthens our hypothesis that this signature is only enriched in studies that demonstrated protection. This gene signature was enriched in the partially effective RV144 human trial that administered the ALVAC/protein vaccine, and we find that the signature associates with both decreased risk of HIV-1 acquisition and increased vaccine efficacy. Total RNA-seq in a clinical trial that used the same vaccine regimen as the RV144 HIV vaccine implicated antibody-dependent cellular phagocytosis (ADCP) as a potential mechanism of vaccine protection. CITE-seq profiling of 53 surface markers and transcriptomes of 53,777 single cells from the same trial showed that genes in this signature were primarily expressed in cells belonging to the myeloid lineage, including monocytes, which are major effector cells for ADCP. The consistent association of this transcriptome signature with vaccine efficacy represents a tool both to identify potential mechanisms, as with ADCP here, and to screen novel approaches to accelerate development of new vaccine candidates.
Data availability
All code and data generated or analyzed during this study are included with the manuscript and supporting files. Source data files have been provided for all data used in this study, including CITE-seq and gene expression matrix for all studies are available at figshare 10.6084/m9.figshare.14555958. The RNA-seq gene expression data for RV306 and HVTN 505 studies are available in the National Center for Biotechnology Information Gene Expression Omnibus (GEO) under accession numbers: "GSE181932" and "GS1E181859" respectively. Dataset from GSE181932 can be accessed at URL https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE181932with reviewer token mnyxkcgedbqdnch.Dataset from GSE181859 can be accessed at URL https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE181859with reviewer token etuhyseoxrghxkd.
Article and author information
Author details
Funding
Henry M. Jackson Foundation (W81XWH-07-2-0067)
- Shida Shangguan
- Philip K Ehrenberg
- Aviva Geretz
- Lauren Yum
- Gautam Kundu
- Kelly May
- Eric Lewitus
- Morgane Rolland
- Nelson L Michael
- Sandhya Vasan
- Rasmi Thomas
National Institute of Allergy and Infectious Diseases
- Shida Shangguan
- Philip K Ehrenberg
- Aviva Geretz
- Lauren Yum
- Gautam Kundu
- Eric Lewitus
- Morgane Rolland
- Nelson L Michael
- Sandhya Vasan
- Rasmi Thomas
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Mark Marsh, University College London, United Kingdom
Version history
- Received: April 20, 2021
- Preprint posted: May 15, 2021 (view preprint)
- Accepted: September 16, 2021
- Accepted Manuscript published: September 17, 2021 (version 1)
- Version of Record published: October 13, 2021 (version 2)
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Metrics
-
- 1,410
- views
-
- 181
- downloads
-
- 10
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Epidemiology and Global Health
- Microbiology and Infectious Disease
Systematically tracking and analysing reproductive loss in livestock helps with efforts to safeguard the health and productivity of food animals by identifying causes and high-risk areas.
-
- Microbiology and Infectious Disease
Survival of Mycobacterium tuberculosis within the host macrophages requires the bacterial virulence regulator PhoP, but the underlying reason remains unknown. 3′,5′-Cyclic adenosine monophosphate (cAMP) is one of the most widely used second messengers, which impacts a wide range of cellular responses in microbial pathogens including M. tuberculosis. Herein, we hypothesized that intra-bacterial cAMP level could be controlled by PhoP since this major regulator plays a key role in bacterial responses against numerous stress conditions. A transcriptomic analysis reveals that PhoP functions as a repressor of cAMP-specific phosphodiesterase (PDE) Rv0805, which hydrolyzes cAMP. In keeping with these results, we find specific recruitment of the regulator within the promoter region of rv0805 PDE, and absence of phoP or ectopic expression of rv0805 independently accounts for elevated PDE synthesis, leading to the depletion of intra-bacterial cAMP level. Thus, genetic manipulation to inactivate PhoP-rv0805-cAMP pathway decreases cAMP level, stress tolerance, and intracellular survival of the bacillus.