A transmission-virulence evolutionary trade-off explains attenuation of HIV-1 in Uganda
Abstract
Evolutionary theory hypothesizes that intermediate virulence maximizes pathogen fitness as a result of a trade-off between virulence and transmission, but empirical evidence remains scarce. We bridge this gap using data from a large and long-standing HIV-1 prospective cohort, in Uganda. We use an epidemiological-evolutionary model parameterised with this data to derive evolutionary predictions based on analysis and detailed individual-based simulations. We robustly predict stabilising selection towards a low level of virulence, and rapid attenuation of the virus. Accordingly, set-point viral load, the most common measure of virulence, has declined in the last 20 years. Our model also predicts that subtype A is slowly outcompeting subtype D, with both subtypes becoming less virulent, as observed in the data. Reduction of set-point viral loads should have resulted in a 20% reduction in incidence, and a three years extension of untreated asymptomatic infection, increasing opportunities for timely treatment of infected individuals.
Data availability
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Data from: A transmission-virulence evolutionary trade-off explains attenuation of HIV-1 in UgandaAvailable at Dryad Digital Repository under a CC0 Public Domain Dedication.
Article and author information
Author details
Funding
European Commission (Intra European Fellowship 657768)
- François Blanquart
World Bank Group
- Mary Kate Grabowski
- Fred Nalugoda
- David Serwadda
- Michael A Eller
- Merlin L Robb
- Ronald Gray
- Godfrey Kigozi
- Oliver Laeyendecker
- Gertrude Nakigozi
- Thomas C Quinn
- Steven J Reynolds
- Maria J Wawer
Henry M. Jackson Foundation (W81XWH-07-2-0067)
- Mary Kate Grabowski
- Fred Nalugoda
- David Serwadda
- Michael A Eller
- Merlin L Robb
- Ronald Gray
- Godfrey Kigozi
- Oliver Laeyendecker
- Gertrude Nakigozi
- Thomas C Quinn
- Steven J Reynolds
- Maria J Wawer
U.S. Department of Defense (W81XWH-07-2-0067)
- Mary Kate Grabowski
- Fred Nalugoda
- David Serwadda
- Michael A Eller
- Merlin L Robb
- Ronald Gray
- Godfrey Kigozi
- Oliver Laeyendecker
- Gertrude Nakigozi
- Thomas C Quinn
- Steven J Reynolds
- Maria J Wawer
National Institutes of Health (R01AI108490; P30AI027757)
- Joshua Herbeck
European Research Council (PBDR-339251)
- Christophe Fraser
National Institute of Allergy and Infectious Diseases (R01 Al 29314; R01 AI34826; UO1 AI11171-01-02)
- Mary Kate Grabowski
- Fred Nalugoda
- David Serwadda
- Michael A Eller
- Merlin L Robb
- Ronald Gray
- Godfrey Kigozi
- Oliver Laeyendecker
- Gertrude Nakigozi
- Thomas C Quinn
- Steven J Reynolds
- Maria J Wawer
National Institute of Child Health and Human Development (5P30 HD 06268)
- Mary Kate Grabowski
- Fred Nalugoda
- David Serwadda
- Michael A Eller
- Merlin L Robb
- Ronald Gray
- Godfrey Kigozi
- Oliver Laeyendecker
- Gertrude Nakigozi
- Thomas C Quinn
- Steven J Reynolds
- Maria J Wawer
John E. Fogarty Foundation for Persons with Intellectual and Developmental Disabilities (5D43TW00010)
- Mary Kate Grabowski
- Fred Nalugoda
- David Serwadda
- Michael A Eller
- Merlin L Robb
- Ronald Gray
- Godfrey Kigozi
- Oliver Laeyendecker
- Gertrude Nakigozi
- Thomas C Quinn
- Steven J Reynolds
- Maria J Wawer
John Snow Inc. (5024-30)
- Mary Kate Grabowski
- Fred Nalugoda
- David Serwadda
- Michael A Eller
- Merlin L Robb
- Ronald Gray
- Godfrey Kigozi
- Oliver Laeyendecker
- Gertrude Nakigozi
- Thomas C Quinn
- Steven J Reynolds
- Maria J Wawer
Pfizer (5024-30)
- Mary Kate Grabowski
- Fred Nalugoda
- David Serwadda
- Michael A Eller
- Merlin L Robb
- Ronald Gray
- Godfrey Kigozi
- Oliver Laeyendecker
- Gertrude Nakigozi
- Thomas C Quinn
- Steven J Reynolds
- Maria J Wawer
Rockefeller Foundation
- Mary Kate Grabowski
- Fred Nalugoda
- David Serwadda
- Michael A Eller
- Merlin L Robb
- Ronald Gray
- Godfrey Kigozi
- Oliver Laeyendecker
- Gertrude Nakigozi
- Thomas C Quinn
- Steven J Reynolds
- Maria J Wawer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Richard A Neher, Max Planck Institute for Developmental Biology, Germany
Ethics
Human subjects: Informed consent was obtained from all the participants in the Rakai Community Cohort Study.The Scientific and Ethics Committee of the Uganda Virus Research Institute (UVRI) of the Ministry of Health provides the Institutional Review Board approval and monitoring of all Rakai research.
Version history
- Received: August 10, 2016
- Accepted: November 1, 2016
- Accepted Manuscript published: November 5, 2016 (version 1)
- Accepted Manuscript updated: November 8, 2016 (version 2)
- Version of Record published: November 18, 2016 (version 3)
Copyright
© 2016, Blanquart 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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Further reading
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- Epidemiology and Global Health
Paxlovid, a SARS-CoV-2 antiviral, not only prevents severe illness but also curtails viral shedding, lowering transmission risks from treated patients. By fitting a mathematical model of within-host Omicron viral dynamics to electronic health records data from 208 hospitalized patients in Hong Kong, we estimate that Paxlovid can inhibit over 90% of viral replication. However, its effectiveness critically depends on the timing of treatment. If treatment is initiated three days after symptoms first appear, we estimate a 17% chance of a post-treatment viral rebound and a 12% (95% CI: 0%-16%) reduction in overall infectiousness for non-rebound cases. Earlier treatment significantly elevates the risk of rebound without further reducing infectiousness, whereas starting beyond five days reduces its efficacy in curbing peak viral shedding. Among the 104 patients who received Paxlovid, 62% began treatment within an optimal three-to-five-day day window after symptoms appeared. Our findings indicate that broader global access to Paxlovid, coupled with appropriately timed treatment, can mitigate the severity and transmission of SARS-Cov-2.
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- Epidemiology and Global Health
Background:
Circulating omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) have been associated with various chronic diseases and mortality, but results are conflicting. Few studies examined the role of omega-6/omega-3 ratio in mortality.
Methods:
We investigated plasma omega-3 and omega-6 PUFAs and their ratio in relation to all-cause and cause-specific mortality in a large prospective cohort, the UK Biobank. Of 85,425 participants who had complete information on circulating PUFAs, 6461 died during follow-up, including 2794 from cancer and 1668 from cardiovascular disease (CVD). Associations were estimated by multivariable Cox proportional hazards regression with adjustment for relevant risk factors.
Results:
Risk for all three mortality outcomes increased as the ratio of omega-6/omega-3 PUFAs increased (all Ptrend <0.05). Comparing the highest to the lowest quintiles, individuals had 26% (95% CI, 15–38%) higher total mortality, 14% (95% CI, 0–31%) higher cancer mortality, and 31% (95% CI, 10–55%) higher CVD mortality. Moreover, omega-3 and omega-6 PUFAs in plasma were all inversely associated with all-cause, cancer, and CVD mortality, with omega-3 showing stronger effects.
Conclusions:
Using a population-based cohort in UK Biobank, our study revealed a strong association between the ratio of circulating omega-6/omega-3 PUFAs and the risk of all-cause, cancer, and CVD mortality.
Funding:
Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institute of Health under the award number R35GM143060 (KY). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.