Predictors of SIV recrudescence following antiretroviral treatment interruption
- University of New South Wales, Australia
- Frederick National Laboratory for Cancer Research, United States
Abstract
There is currently a need for proxy measures of the HIV rebound competent reservoir (RCR) that can predict viral rebound after combined antiretroviral treatment (cART) interruption. In this study, macaques infected with a barcoded SIVmac239 virus received cART beginning between 4- and 27-days post-infection, leading to the establishment of different levels of viral dissemination and persistence. Later treatment initiation led to higher SIV DNA levels maintained during treatment, which was significantly associated with an increased frequency of SIV reactivation and production of progeny capable of causing rebound viremia following treatment interruption. However, a 100-fold increase in SIV DNA in PBMCs was associated with only a 2-fold increase in the frequency of reactivation. These data suggest that the RCR can be established soon after infection, and that a large fraction of persistent viral DNA that accumulates after this time makes relatively little contribution to viral rebound.
Data availability
Source data files have been provided for Figures.
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Genetically-barcoded SIV facilitates enumeration of rebound variants and estimation of reactivation rates in nonhuman primates following interruption of suppressive antiretroviral therapy.https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006359#sec025.
Article and author information
Author details
Funding
National Institutes of Health (HHSN261200800001E)
- Christine M Fennessey
- Carolyn Reid
- Charles M Trubey
- Jeffrey D Lifson
- Brandon F Keele
National Health and Medical Research Council (1052979)
- Mykola Pinkevych
- Deborah Cromer
- Miles P Davenport
National Health and Medical Research Council (1149990)
- Mykola Pinkevych
- Deborah Cromer
- Miles P Davenport
National Health and Medical Research Council (1080001)
- Miles P Davenport
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animals were cared for in accordance with the Association for the Assessment and Accreditation of Laboratory Animal Care (AAALAC) standards in an AAALAC-accredited facility and all procedures were performed according to protocols approved by the Institutional Animal Care and Use Committee of the National Cancer Institute (Assurance #A4149-01). Animal care was provided in accordance with the procedures outlined in the "Guide for Care and Use of Laboratory Animals". Reference numbers associated with the ethical approval are AVP047 and AVP058.
Reviewing Editor
- Frank Kirchhoff, Ulm University Medical Center, Germany
Publication history
- Received: June 4, 2019
- Accepted: October 24, 2019
- Accepted Manuscript published: October 25, 2019 (version 1)
- Version of Record published: December 17, 2019 (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.
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Predictors of SIV recrudescence following antiretroviral treatment interruption
eLife 8:e49022.
https://doi.org/10.7554/eLife.49022
Further reading
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African trypanosomes proliferate as bloodstream forms (BSFs) and procyclic forms in the mammal and tsetse fly midgut, respectively. This allows them to colonise the host environment upon infection and ensure life cycle progression. Yet, understanding of the mechanisms that regulate and drive the cell replication cycle of these forms is limited. Using single-cell transcriptomics on unsynchronised cell populations, we have obtained high resolution cell cycle regulated (CCR) transcriptomes of both procyclic and slender BSF Trypanosoma brucei without prior cell sorting or synchronisation. Additionally, we describe an efficient freeze–thawing protocol that allows single-cell transcriptomic analysis of cryopreserved T. brucei. Computational reconstruction of the cell cycle using periodic pseudotime inference allowed the dynamic expression patterns of cycling genes to be profiled for both life cycle forms. Comparative analyses identify a core cycling transcriptome highly conserved between forms, as well as several genes where transcript levels dynamics are form specific. Comparing transcript expression patterns with protein abundance revealed that the majority of genes with periodic cycling transcript and protein levels exhibit a relative delay between peak transcript and protein expression. This work reveals novel detail of the CCR transcriptomes of both forms, which are available for further interrogation via an interactive webtool.
