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.
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.
Reviewing Editor
- Julie Overbaugh, Fred Hutchinson Cancer Research Center, United States
Publication 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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Background: Although inactivated COVID-19 vaccines are proven to be safe and effective in the general population, the dynamic response and duration of antibodies after vaccination in the real world should be further assessed.
Methods: We enrolled 1067 volunteers who had been vaccinated with one or two doses of CoronaVac in Zhejiang Province, China. Another 90 healthy adults without previous vaccinations were recruited and vaccinated with three doses of CoronaVac, 28 days and 6 months apart. Serum samples were collected from multiple timepoints and analyzed for specific IgM/IgG and neutralizing antibodies (NAbs) for immunogenicity evaluation. Antibody responses to the Delta and Omicron variants were measured by pseudovirus-based neutralization tests.
Results: Our results revealed that binding antibody IgM peaked 14-28 days after one dose of CoronaVac, while IgG and NAbs peaked approximately 1 month after the second dose then declined slightly over time. Antibody responses had waned by month 6 after vaccination and became undetectable in the majority of individuals at 12 months. Levels of NAbs to live SARS-CoV-2 were correlated with anti-SARS-CoV-2 IgG and NAbs to pseudovirus, but not IgM. Homologous booster around 6 months after primary vaccination activated anamnestic immunity and raised NAbs 25.5-fold. The neutralized fraction subsequently rose to 36.0% for Delta (p=0.03) and 4.3% for Omicron (p=0.004), and the response rate for Omicron rose from 7.9% (7/89) to 17.8% (16/90).
Conclusions: Two doses of CoronaVac vaccine resulted in limited protection over a short duration. The inactivated vaccine booster can reverse the decrease of antibody levels to prime strain, but it does not elicit potent neutralization against Omicron; therefore, the optimization of booster procedures is vital.
Funding: Key Research and Development Program of Zhejiang Province; Key Program of Health Commission of Zhejiang Province/ Science Foundation of National Health Commission; Major Program of Zhejiang Municipal Natural Science Foundation; Explorer Program of Zhejiang Municipal Natural Science Foundation.
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