The HIV-1 latent reservoir is largely sensitive to circulating T cells
- University of North Carolina at Chapel Hill, United States
- British Columbia Centre for Excellence in HIV/AIDS, Canada
- University of California, San Francisco, United States
Abstract
HIV-1 specific CD8+ T cells are an important component of HIV-1 curative strategies. Viral variants in the HIV-1 reservoir may limit the capacity of T cells to detect and clear virus-infected cells. We investigated the patterns of T cell escape variants in the replication-competent reservoir of 25 persons living with HIV-1 (PLWH) durably suppressed on ART. We identified all reactive T cell epitopes in the HIV-1 proteome for each participant and sequenced HIV-1 outgrowth viruses from resting CD4+ T cells. All non-synonymous mutations in reactive T cell epitopes were tested for their effect on the size of the T cell response, with a ≥50% loss defined as an escape mutation. The majority (68%) of T cell epitopes harbored no detectable escape mutations. These findings suggest that circulating T cells in PLWH on ART could contribute to control of rebound and could be targeted for boosting in curative strategies.
Data availability
Sequencing data have been deposited in Gen Bank under PRJNA666896, MT307344-MT308415 and MW054719-MW054856All data generated (raw) or analyzed during this study are included in the manuscript and supporting files (supplemental files).
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Primer ID sequencing for QVOA HIV sequenceNCBI Bioproject, PRJNA666896.
Article and author information
Author details
Funding
National Institute of Allergy and Infectious Diseases (P30 AI50410)
- Ronald Swanstrom
National Institute of Allergy and Infectious Diseases (U01 AI103390)
- Adaora A Adimora
National Institute of Allergy and Infectious Diseases (U01 AI034989)
- Nadia Roan
National Institute of Allergy and Infectious Diseases (U01 AI131310)
- Joanna A Warren
- Shuntai Zhou
- Yinyan Xu
- Nilu Goonetilleke
National Institute of Allergy and Infectious Diseases (R01 AI140970)
- Ronald Swanstrom
National Institute of Allergy and Infectious Diseases (UM1AI126617)
- Daniel R MacMillan
- Zabrina L Brumme
National Institute of Allergy and Infectious Diseases (1UM1AI126619)
- Joanna A Warren
- Shuntai Zhou
- Julia M Sung
- JoAnn D Kuruc
- Cynthia L Gay
- David M Margolis
- Nancie Archin
- Nilu Goonetilleke
Canadian Institutes of Health Research (PJT-148612)
- Daniel R MacMillan
- Zabrina L Brumme
Canadian Institutes of Health Research (PJT-159625)
- Daniel R MacMillan
- Zabrina L Brumme
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Julie Overbaugh, Fred Hutchinson Cancer Research Center, United States
Ethics
Human subjects: Participants were enrolled with the following IRB approved studies: 1) CID 0819 - Apheresis Procedures to Obtain Leukocytes for Research Studies from HIV Positive Participants (08-1575), 2) The UNC Women's Interagency HIV Study (WIHS) (12-1660). Review and implementation of all protocols utilized for the collection of samples for this this analysis were approved by the University of North Carolina at Chapel Hill Biomedical Institutional Review Board (IRB) and the University of California at San Francisco IRB. All participants provided written informed consent. All experimental protocols were approved by local Institutional Biomedical Review Boards (ethics numbers: 14-0741, 11-0228, and 13-3613, 15-1626) and performed in accordance with the relevant guidelines.
Version history
- Received: March 26, 2020
- Accepted: September 24, 2020
- Accepted Manuscript published: October 6, 2020 (version 1)
- Version of Record published: October 28, 2020 (version 2)
Copyright
© 2020, Warren et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The HIV-1 latent reservoir is largely sensitive to circulating T cells
eLife 9:e57246.
https://doi.org/10.7554/eLife.57246
Further reading
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- Evolutionary Biology
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CD4+ T cell activation is driven by five-module receptor complexes. The T cell receptor (TCR) is the receptor module that binds composite surfaces of peptide antigens embedded within MHCII molecules (pMHCII). It associates with three signaling modules (CD3γε, CD3δε, and CD3ζζ) to form TCR-CD3 complexes. CD4 is the coreceptor module. It reciprocally associates with TCR-CD3-pMHCII assemblies on the outside of a CD4+ T cells and with the Src kinase, LCK, on the inside. Previously, we reported that the CD4 transmembrane GGXXG and cytoplasmic juxtamembrane (C/F)CV+C motifs found in eutherian (placental mammal) CD4 have constituent residues that evolved under purifying selection (Lee et al., 2022). Expressing mutants of these motifs together in T cell hybridomas increased CD4-LCK association but reduced CD3ζ, ZAP70, and PLCγ1 phosphorylation levels, as well as IL-2 production, in response to agonist pMHCII. Because these mutants preferentially localized CD4-LCK pairs to non-raft membrane fractions, one explanation for our results was that they impaired proximal signaling by sequestering LCK away from TCR-CD3. An alternative hypothesis is that the mutations directly impacted signaling because the motifs normally play an LCK-independent role in signaling. The goal of this study was to discriminate between these possibilities. Using T cell hybridomas, our results indicate that: intracellular CD4-LCK interactions are not necessary for pMHCII-specific signal initiation; the GGXXG and (C/F)CV+C motifs are key determinants of CD4-mediated pMHCII-specific signal amplification; the GGXXG and (C/F)CV+C motifs exert their functions independently of direct CD4-LCK association. These data provide a mechanistic explanation for why residues within these motifs are under purifying selection in jawed vertebrates. The results are also important to consider for biomimetic engineering of synthetic receptors.
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- Genetics and Genomics
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Transposable elements (TEs) are repetitive sequences representing ~45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTECs). In this study, we investigated the role of TEs on T-cell development in the thymus. We performed multiomic analyses of TEs in human and mouse thymic cells to elucidate their role in T-cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TE expression correlates with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDCs). In mTECs, transcriptomic data suggest that TEs interact with transcription factors essential for mTEC development and function (e.g., PAX1 and REL), and immunopeptidomic data showed that TEs generate MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 regulate small yet non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large numbers of TEs that likely form dsRNA, which can activate innate immune receptors, potentially explaining why thymic pDCs constitutively secrete IFN ɑ/β. This study highlights the diversity of interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. Therefore, we propose that orchestrating TE expression in thymic cells is critical to prevent autoimmunity in vertebrates.
