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Evolutionary genetics of HIV-1: Exploring evolution on complex fitness landscapes

English title Evolutionary genetics of HIV-1: Exploring evolution on complex fitness landscapes
Applicant Bonhoeffer Sebastian
Number 133129
Funding scheme Project funding (special)
Research institution Gruppe Theoretische Biologie Departement Umweltsystemwissenschaften ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Ecology
Start/End 01.01.2011 - 31.03.2014
Approved amount 498'284.00
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All Disciplines (2)

Discipline
Ecology
Infectious Diseases

Keywords (7)

evolutionary genetics; HIV; drug resistance; fitness landscapes; antiretroviral inhibitors; large nested project; Swiss HIV Cohort Study

Lay Summary (English)

Lead
Lay summary
This research is the continuation of an earlier grant (31003A-116408 "Evolution of recombination from a retroviral perspective: Mathematical models and data analysis"). A key aspect was the development of a statistical model that allows estimating the fitness effects of individual mutations and combinations of mutations in HIV-1 protease and reverse transcriptase based on a large data set of in vitro fitness measurements of HIV-1 in 16 different environments (no drug and 15 individuals drugs). Here we use these models to predict replicative fitness of HIV and explore the properties of the estimated fitness landscapes. The grant is subdivided into three subprojects.In the first part we plan to test the correlation between our predicted fitness with virus load observed in patients enrolled in the Swiss HIV Cohort Study. In the second part we aim to characterize the general properties of the fitness landscape underlying HIV-1 reverse transcriptase and protease. In the third part we aim to develop better generic models for fitness landscapes based on the insights gained from the HIV fitness landscape.
Direct link to Lay Summary Last update: 21.02.2013

Employees

Publications

Publication
Using an epidemiological model for phylogenetic inference reveals density dependence in HIV transmission.
Leventhal Gabriel E, Günthard Huldrych F, Bonhoeffer Sebastian, Stadler Tanja (2014), Using an epidemiological model for phylogenetic inference reveals density dependence in HIV transmission., in Mol Biol Evol, 6-15.
Virulence and pathogenesis of HIV-1 infection: an evolutionary perspective.
Fraser Christophe, Lythgoe Katrina, Leventhal Gabriel E, Shirreff George, Hollingsworth T Deirdre, Alizon Samuel, Bonhoeffer Sebastian (2014), Virulence and pathogenesis of HIV-1 infection: an evolutionary perspective., in Science, ---.
Birth-death skyline plot reveals temporal changes of epidemic spread in HIV and hepatitis C virus (HCV).
Stadler Tanja, Kühnert Denise, Bonhoeffer Sebastian, Drummond Alexei J (2013), Birth-death skyline plot reveals temporal changes of epidemic spread in HIV and hepatitis C virus (HCV)., in Proc Natl Acad Sci U S A, 228-233.
Fixation probability of mobile genetic elements such as plasmids.
Tazzyman Samuel J, Bonhoeffer Sebastian (2013), Fixation probability of mobile genetic elements such as plasmids., in Theor Popul Biol, 49-55.
Virus-induced target cell activation reconciles set-point viral load heritability and within-host evolution.
Hool Anna, Leventhal Gabriel E, Bonhoeffer Sebastian (2013), Virus-induced target cell activation reconciles set-point viral load heritability and within-host evolution., in Epidemics, 174-180.
Assessing the impact of adherence to anti-retroviral therapy on treatment failure and resistance evolution in HIV.
Cadosch Dominique, Bonhoeffer Sebastian, Kouyos Roger (2012), Assessing the impact of adherence to anti-retroviral therapy on treatment failure and resistance evolution in HIV., in Journal of the Royal Society, Interface / the Royal Society, 9(74), 2309-20.
Assessing the impact of adherence to anti-retroviral therapy on treatment failure and resistance evolution in HIV.
Cadosch Dominique, Bonhoeffer Sebastian, Kouyos Roger (2012), Assessing the impact of adherence to anti-retroviral therapy on treatment failure and resistance evolution in HIV., in J R Soc Interface, 2309-2320.
Estimating the basic reproductive number from viral sequence data.
Stadler Tanja, Kouyos Roger, von Wyl Viktor, Yerly Sabine, Böni Jürg, Bürgisser Philippe, Klimkait Thomas, Joos Beda, Rieder Philip, Xie Dong, Günthard Huldrych F, Drummond Alexei J, Bonhoeffer Sebastian, Study Swiss HIV Cohort (2012), Estimating the basic reproductive number from viral sequence data., in Mol Biol Evol, 347-357.
Estimating the fitness cost of escape from HLA presentation in HIV-1 protease and reverse transcriptase.
Mostowy Rafal, Kouyos Roger D, Hoof Ilka, Hinkley Trevor, Haddad Mojgan, Whitcomb Jeannette M, Petropoulos Christos J, Ke{ç s}mir Can, Bonhoeffer Sebastian (2012), Estimating the fitness cost of escape from HLA presentation in HIV-1 protease and reverse transcriptase., in PLoS Comput Biol, ---.
Exploring the Complexity of the HIV-1 Fitness Landscape
Kouyos RD, Leventhal GE, Hinkley T, Haddad M, Whitcomb JM, Petropoulos CJ, Bonhoeffer S (2012), Exploring the Complexity of the HIV-1 Fitness Landscape, in PLOS GENETICS, 8(3), 1-1.
Inferring Epidemic Contact Structure from Phylogenetic Trees
Leventhal GE, Kouyos R, Stadler T, von Wyl V, Yerly S, Boni J, Cellerai C, Klimkait T, Gunthard HF, Bonhoeffer S (2012), Inferring Epidemic Contact Structure from Phylogenetic Trees, in PLOS COMPUTATIONAL BIOLOGY, 8(3), 1-1.
Pre-existence and emergence of drug resistance in a generalized model of intra-host viral dynamics.
Alexander Helen K, Bonhoeffer Sebastian (2012), Pre-existence and emergence of drug resistance in a generalized model of intra-host viral dynamics., in Epidemics, 187-202.
Assessing Predicted HIV-1 Replicative Capacity in a Clinical Setting
Kouyos RD, von Wyl V, Hinkley T, Petropoulos CJ, Haddad M, Whitcomb JM, Boni J, Yerly S, Cellerai C, Klimkait T, Gunthard HF, Bonhoeffer S (2011), Assessing Predicted HIV-1 Replicative Capacity in a Clinical Setting, in PLOS PATHOGENS, 7(11), 1-1.

Collaboration

Group / person Country
Types of collaboration
Monogram Biosciences United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Industry/business/other use-inspired collaboration
Universität Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
116408 Evolution of recombination from a retroviral perspective: Mathematical models and data analysis 01.01.2008 Project funding

Abstract

The work outlined here represents a continuation of the SNF grant 31003A-116408 “Evolution of recombination from a retroviral perspective: Mathematical models and data analysis”. A major component of this grant was to develop a statistical model that allows estimating the fitness effects of individual mutations and combinations of mutations in HIV-1 protease and reverse transcriptase based on a large data set of in vitro fitness measurements of HIV-1 in 16 different environments (no drug and 15 individuals drugs). We have now successfully developed such models (Hinkley et al, 2010, under revision). These models predict 40%-60% of the variation in fitness of the in vitro fitness estimates from the amino acid sequence of reverse transcriptase and protease. Our models thus represent a good approximation to the fitness landscapes underlying HIV-1 protease and reverse transcriptase in different environments. The goal of this continuation grant is to built onto this work and explore the properties of the estimated fitness landscapes.
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