A transmission-virulence evolutionary trade-off explains attenuation of HIV-1 in Uganda
- Imperial College London, United Kingdom
- Johns Hopkins University, United States
- University of Washington, United States
- Rakai Health Sciences Program, Uganda
- Walter Reed Army Institute of Research, United States
- National Institutes of Health, United States
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
François Blanquart
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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A transmission-virulence evolutionary trade-off explains attenuation of HIV-1 in Uganda
eLife 5:e20492.
https://doi.org/10.7554/eLife.20492
Further reading
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- Epidemiology and Global Health
Background:
The Zanzibar archipelago of Tanzania has become a low-transmission area for Plasmodium falciparum. Despite being considered an area of pre-elimination for years, achieving elimination has been difficult, likely due to a combination of imported infections from mainland Tanzania and continued local transmission.
Methods:
To shed light on these sources of transmission, we applied highly multiplexed genotyping utilizing molecular inversion probes to characterize the genetic relatedness of 282 P. falciparum isolates collected across Zanzibar and in Bagamoyo district on the coastal mainland from 2016 to 2018.
Results:
Overall, parasite populations on the coastal mainland and Zanzibar archipelago remain highly related. However, parasite isolates from Zanzibar exhibit population microstructure due to the rapid decay of parasite relatedness over very short distances. This, along with highly related pairs within shehias, suggests ongoing low-level local transmission. We also identified highly related parasites across shehias that reflect human mobility on the main island of Unguja and identified a cluster of highly related parasites, suggestive of an outbreak, in the Micheweni district on Pemba island. Parasites in asymptomatic infections demonstrated higher complexity of infection than those in symptomatic infections, but have similar core genomes.
Conclusions:
Our data support importation as a main source of genetic diversity and contribution to the parasite population in Zanzibar, but they also show local outbreak clusters where targeted interventions are essential to block local transmission. These results highlight the need for preventive measures against imported malaria and enhanced control measures in areas that remain receptive to malaria reemergence due to susceptible hosts and competent vectors.
Funding:
This research was funded by the National Institutes of Health, grants R01AI121558, R01AI137395, R01AI155730, F30AI143172, and K24AI134990. Funding was also contributed from the Swedish Research Council, Erling-Persson Family Foundation, and the Yang Fund. RV acknowledges funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/R015600/1), jointly funded by the UK Medical Research Council (MRC) and the UK Foreign, Commonwealth & Development Office (FCDO), under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 program supported by the European Union. RV also acknowledges funding by Community Jameel.
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- Computational and Systems Biology
- Epidemiology and Global Health
The chemical composition of foods is complex, variable, and dependent on many factors. This has a major impact on nutrition research as it foundationally affects our ability to adequately assess the actual intake of nutrients and other compounds. In spite of this, accurate data on nutrient intake are key for investigating the associations and causal relationships between intake, health, and disease risk at the service of developing evidence-based dietary guidance that enables improvements in population health. Here, we exemplify the importance of this challenge by investigating the impact of food content variability on nutrition research using three bioactives as model: flavan-3-ols, (–)-epicatechin, and nitrate. Our results show that common approaches aimed at addressing the high compositional variability of even the same foods impede the accurate assessment of nutrient intake generally. This suggests that the results of many nutrition studies using food composition data are potentially unreliable and carry greater limitations than commonly appreciated, consequently resulting in dietary recommendations with significant limitations and unreliable impact on public health. Thus, current challenges related to nutrient intake assessments need to be addressed and mitigated by the development of improved dietary assessment methods involving the use of nutritional biomarkers.
