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.
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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- Microbiology and Infectious Disease
The persistence of latent viral reservoirs remains the major obstacle to eradicating human immunodeficiency virus (HIV). We herein found that ICP34.5 can act as an antagonistic factor for the reactivation of HIV latency by herpes simplex virus type I (HSV-1), and thus recombinant HSV-1 with ICP34.5 deletion could more effectively reactivate HIV latency than its wild-type counterpart. Mechanistically, HSV-ΔICP34.5 promoted the phosphorylation of HSF1 by decreasing the recruitment of protein phosphatase 1 (PP1α), thus effectively binding to the HIV LTR to reactivate the latent reservoirs. In addition, HSV-ΔICP34.5 enhanced the phosphorylation of IKKα/β through the degradation of IκBα, leading to p65 accumulation in the nucleus to elicit NF-κB pathway-dependent reactivation of HIV latency. Then, we constructed the recombinant HSV-ΔICP34.5 expressing simian immunodeficiency virus (SIV) env, gag, or the fusion antigen sPD1-SIVgag as a therapeutic vaccine, aiming to achieve a functional cure by simultaneously reactivating viral latency and eliciting antigen-specific immune responses. Results showed that these constructs effectively elicited SIV-specific immune responses, reactivated SIV latency, and delayed viral rebound after the interruption of antiretroviral therapy (ART) in chronically SIV-infected rhesus macaques. Collectively, these findings provide insights into the rational design of HSV-vectored therapeutic strategies for pursuing an HIV functional cure.
