The Contribution of Viral Genotype to Plasma Viral Set-Point in HIV Infection

Emma Hodcroft; Jarrod D. Hadfield; Esther Fearnhill; Andrew Phillips; David Dunn; Siobhan O'Shea; Deenan Pillay; Andrew J. Leigh Brown; Aitken Celia; Asboe David; Pozniak Anton; Patricia Cane; Castro Hannah; Dunn David; Fearnhill Esther; Porter Kholoud; Chadwick David; Churchill Duncan; Clark Duncan; Collins Simon; Delpech Valerie; Douthwaite Samuel; Maria Geretti Anna; Hale Antony; Hué Stéphane; Kaye Steve; Kellam Paul; Lazarus Linda; Leigh Brown Andrew; Mbisa Tamyo; Mackie Nicola; Orkin Chloe; Nastouli Eleni; Pillay Deenan; Phillips Andrew; Sabin Caroline; Smit Erasmus; Templeton Kate; Tilston Peter; Webster Daniel; Williams Ian; Zhang Hongyi; Zuckerman Mark; Ainsworth Jonathan; Allan Sris; Anderson Jane; Babiker Abdel; Chadwick David; Dunn David; Fisher Martin; Gazzard (Chair) Brian; Gilson Richard; Gompels Mark; Hay Phillip; Hill Teresa; Johnson Margaret; Kegg Stephen; Leen Clifford; Martin Fabiola; Nelson Mark; Orkin Chloe; Palfreeman Adrian; Phillips Andrew; Pillay Deenan; Pritchard Jillian; Post Frank; Sabin Caroline; Sachikonye Memory; Schwenk Achim; Tariq Anjum; Walsh John

doi:10.1371/journal.ppat.1004112

The Contribution of Viral Genotype to Plasma Viral Set-Point in HIV Infection

Emma Hodcroft, Jarrod D. Hadfield, Esther Fearnhill, Andrew Phillips, David Dunn, Siobhan O'Shea, Deenan Pillay, Andrew J. Leigh Brown, Aitken Celia, Asboe David, Pozniak Anton, Patricia Cane, Castro Hannah, Dunn David, Fearnhill Esther, Porter Kholoud, Chadwick David, Churchill Duncan, Clark Duncan, Collins SimonDelpech Valerie, Douthwaite Samuel, Maria Geretti Anna, Hale Antony, Hué Stéphane, Kaye Steve, Kellam Paul, Lazarus Linda, Leigh Brown Andrew, Mbisa Tamyo, Mackie Nicola, Orkin Chloe, Nastouli Eleni, Pillay Deenan, Phillips Andrew, Sabin Caroline, Smit Erasmus, Templeton Kate, Tilston Peter, Webster Daniel, Williams Ian, Zhang Hongyi, Zuckerman Mark, Ainsworth Jonathan, Allan Sris, Anderson Jane, Babiker Abdel, Chadwick David, Dunn David, Fisher Martin, Gazzard (Chair) Brian, Gilson Richard, Gompels Mark, Hay Phillip, Hill Teresa, Johnson Margaret, Kegg Stephen, Leen Clifford, Martin Fabiola, Nelson Mark, Orkin Chloe, Palfreeman Adrian, Phillips Andrew, Pillay Deenan, Pritchard Jillian, Post Frank, Sabin Caroline, Sachikonye Memory, Schwenk Achim, Tariq Anjum, Walsh John

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Abstract

Disease progression in HIV-infected individuals varies greatly, and while the environmental and host factors influencing this variation have been widely investigated, the viral contribution to variation in set-point viral load, a predictor of disease progression, is less clear. Previous studies, using transmission-pairs and analysis of phylogenetic signal in small numbers of individuals, have produced a wide range of viral genetic effect estimates. Here we present a novel application of a population-scale method based in quantitative genetics to estimate the viral genetic effect on set-point viral load in the UK subtype B HIV-1 epidemic, based on a very large data set. Analyzing the initial viral load and associated pol sequence, both taken before anti-retroviral therapy, of 8,483 patients, we estimate the proportion of variance in viral load explained by viral genetic effects to be 5.7% (CI 2.8-8.6%). We also estimated the change in viral load over time due to selection on the virus and environmental effects to be a decline of 0.05 log₁₀ copies/mL/year, in contrast to recent studies which suggested a reported small increase in viral load over the last 20 years might be due to evolutionary changes in the virus. Our results suggest that in the UK epidemic, subtype B has a small but significant viral genetic effect on viral load. By allowing the analysis of large sample sizes, we expect our approach to be applicable to the estimation of the genetic contribution to traits in many organisms.

Original language	English
Article number	e1004112
Journal	PLoS Pathogens
Volume	10
Issue number	5
DOIs	https://doi.org/10.1371/journal.ppat.1004112
Publication status	Published - May 2014

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Copyright 2014 Elsevier B.V., All rights reserved.

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Hodcroft, E., Hadfield, J. D., Fearnhill, E., Phillips, A., Dunn, D., O'Shea, S., Pillay, D., Leigh Brown, A. J., Celia, A., David, A., Anton, P., Cane, P., Hannah, C., David, D., Esther, F., Kholoud, P., David, C., Duncan, C., Duncan, C., ... John, W. (2014). The Contribution of Viral Genotype to Plasma Viral Set-Point in HIV Infection. PLoS Pathogens, 10(5), Article e1004112. https://doi.org/10.1371/journal.ppat.1004112

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title = "The Contribution of Viral Genotype to Plasma Viral Set-Point in HIV Infection",

abstract = "Disease progression in HIV-infected individuals varies greatly, and while the environmental and host factors influencing this variation have been widely investigated, the viral contribution to variation in set-point viral load, a predictor of disease progression, is less clear. Previous studies, using transmission-pairs and analysis of phylogenetic signal in small numbers of individuals, have produced a wide range of viral genetic effect estimates. Here we present a novel application of a population-scale method based in quantitative genetics to estimate the viral genetic effect on set-point viral load in the UK subtype B HIV-1 epidemic, based on a very large data set. Analyzing the initial viral load and associated pol sequence, both taken before anti-retroviral therapy, of 8,483 patients, we estimate the proportion of variance in viral load explained by viral genetic effects to be 5.7% (CI 2.8-8.6%). We also estimated the change in viral load over time due to selection on the virus and environmental effects to be a decline of 0.05 log10 copies/mL/year, in contrast to recent studies which suggested a reported small increase in viral load over the last 20 years might be due to evolutionary changes in the virus. Our results suggest that in the UK epidemic, subtype B has a small but significant viral genetic effect on viral load. By allowing the analysis of large sample sizes, we expect our approach to be applicable to the estimation of the genetic contribution to traits in many organisms.",

author = "Emma Hodcroft and Hadfield, {Jarrod D.} and Esther Fearnhill and Andrew Phillips and David Dunn and Siobhan O'Shea and Deenan Pillay and {Leigh Brown}, {Andrew J.} and Aitken Celia and Asboe David and Pozniak Anton and Patricia Cane and Castro Hannah and Dunn David and Fearnhill Esther and Porter Kholoud and Chadwick David and Churchill Duncan and Clark Duncan and Collins Simon and Delpech Valerie and Douthwaite Samuel and Anna, {Maria Geretti} and Hale Antony and Hu{\'e} St{\'e}phane and Kaye Steve and Kellam Paul and Lazarus Linda and Andrew, {Leigh Brown} and Mbisa Tamyo and Mackie Nicola and Orkin Chloe and Nastouli Eleni and Pillay Deenan and Phillips Andrew and Sabin Caroline and Smit Erasmus and Templeton Kate and Tilston Peter and Webster Daniel and Williams Ian and Zhang Hongyi and Zuckerman Mark and Ainsworth Jonathan and Allan Sris and Anderson Jane and Babiker Abdel and Chadwick David and Dunn David and Fisher Martin and Brian, {Gazzard (Chair)} and Gilson Richard and Gompels Mark and Hay Phillip and Hill Teresa and Johnson Margaret and Kegg Stephen and Leen Clifford and Martin Fabiola and Nelson Mark and Orkin Chloe and Palfreeman Adrian and Phillips Andrew and Pillay Deenan and Pritchard Jillian and Post Frank and Sabin Caroline and Sachikonye Memory and Schwenk Achim and Tariq Anjum and Walsh John",

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language = "English",

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journal = "PLoS Pathogens",

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Hodcroft, E, Hadfield, JD, Fearnhill, E, Phillips, A, Dunn, D, O'Shea, S, Pillay, D, Leigh Brown, AJ, Celia, A, David, A, Anton, P, Cane, P, Hannah, C, David, D, Esther, F, Kholoud, P, David, C, Duncan, C, Duncan, C, Simon, C, Valerie, D, Samuel, D, Anna, MG, Antony, H, Stéphane, H, Steve, K, Paul, K, Linda, L, Andrew, LB, Tamyo, M, Nicola, M, Chloe, O, Eleni, N, Deenan, P, Andrew, P, Caroline, S, Erasmus, S, Kate, T, Peter, T, Daniel, W, Ian, W, Hongyi, Z, Mark, Z, Jonathan, A, Sris, A, Jane, A, Abdel, B, David, C, David, D, Martin, F, Brian, G, Richard, G, Mark, G, Phillip, H, Teresa, H, Margaret, J, Stephen, K, Clifford, L, Fabiola, M, Mark, N, Chloe, O, Adrian, P, Andrew, P, Deenan, P, Jillian, P, Frank, P, Caroline, S, Memory, S, Achim, S, Anjum, T & John, W 2014, 'The Contribution of Viral Genotype to Plasma Viral Set-Point in HIV Infection', PLoS Pathogens, vol. 10, no. 5, e1004112. https://doi.org/10.1371/journal.ppat.1004112

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T1 - The Contribution of Viral Genotype to Plasma Viral Set-Point in HIV Infection

AU - Hodcroft, Emma

AU - Hadfield, Jarrod D.

AU - Fearnhill, Esther

AU - Phillips, Andrew

AU - Dunn, David

AU - O'Shea, Siobhan

AU - Pillay, Deenan

AU - Leigh Brown, Andrew J.

AU - Celia, Aitken

AU - David, Asboe

AU - Anton, Pozniak

AU - Cane, Patricia

AU - Hannah, Castro

AU - David, Dunn

AU - Esther, Fearnhill

AU - Kholoud, Porter

AU - David, Chadwick

AU - Duncan, Churchill

AU - Duncan, Clark

AU - Simon, Collins

AU - Valerie, Delpech

AU - Samuel, Douthwaite

AU - Anna, Maria Geretti

AU - Antony, Hale

AU - Stéphane, Hué

AU - Steve, Kaye

AU - Paul, Kellam

AU - Linda, Lazarus

AU - Andrew, Leigh Brown

AU - Tamyo, Mbisa

AU - Nicola, Mackie

AU - Chloe, Orkin

AU - Eleni, Nastouli

AU - Deenan, Pillay

AU - Andrew, Phillips

AU - Caroline, Sabin

AU - Erasmus, Smit

AU - Kate, Templeton

AU - Peter, Tilston

AU - Daniel, Webster

AU - Ian, Williams

AU - Hongyi, Zhang

AU - Mark, Zuckerman

AU - Jonathan, Ainsworth

AU - Sris, Allan

AU - Jane, Anderson

AU - Abdel, Babiker

AU - David, Chadwick

AU - David, Dunn

AU - Martin, Fisher

AU - Brian, Gazzard (Chair)

AU - Richard, Gilson

AU - Mark, Gompels

AU - Phillip, Hay

AU - Teresa, Hill

AU - Margaret, Johnson

AU - Stephen, Kegg

AU - Clifford, Leen

AU - Fabiola, Martin

AU - Mark, Nelson

AU - Chloe, Orkin

AU - Adrian, Palfreeman

AU - Andrew, Phillips

AU - Deenan, Pillay

AU - Jillian, Pritchard

AU - Frank, Post

AU - Caroline, Sabin

AU - Memory, Sachikonye

AU - Achim, Schwenk

AU - Anjum, Tariq

AU - John, Walsh

PY - 2014/5

Y1 - 2014/5

N2 - Disease progression in HIV-infected individuals varies greatly, and while the environmental and host factors influencing this variation have been widely investigated, the viral contribution to variation in set-point viral load, a predictor of disease progression, is less clear. Previous studies, using transmission-pairs and analysis of phylogenetic signal in small numbers of individuals, have produced a wide range of viral genetic effect estimates. Here we present a novel application of a population-scale method based in quantitative genetics to estimate the viral genetic effect on set-point viral load in the UK subtype B HIV-1 epidemic, based on a very large data set. Analyzing the initial viral load and associated pol sequence, both taken before anti-retroviral therapy, of 8,483 patients, we estimate the proportion of variance in viral load explained by viral genetic effects to be 5.7% (CI 2.8-8.6%). We also estimated the change in viral load over time due to selection on the virus and environmental effects to be a decline of 0.05 log10 copies/mL/year, in contrast to recent studies which suggested a reported small increase in viral load over the last 20 years might be due to evolutionary changes in the virus. Our results suggest that in the UK epidemic, subtype B has a small but significant viral genetic effect on viral load. By allowing the analysis of large sample sizes, we expect our approach to be applicable to the estimation of the genetic contribution to traits in many organisms.

AB - Disease progression in HIV-infected individuals varies greatly, and while the environmental and host factors influencing this variation have been widely investigated, the viral contribution to variation in set-point viral load, a predictor of disease progression, is less clear. Previous studies, using transmission-pairs and analysis of phylogenetic signal in small numbers of individuals, have produced a wide range of viral genetic effect estimates. Here we present a novel application of a population-scale method based in quantitative genetics to estimate the viral genetic effect on set-point viral load in the UK subtype B HIV-1 epidemic, based on a very large data set. Analyzing the initial viral load and associated pol sequence, both taken before anti-retroviral therapy, of 8,483 patients, we estimate the proportion of variance in viral load explained by viral genetic effects to be 5.7% (CI 2.8-8.6%). We also estimated the change in viral load over time due to selection on the virus and environmental effects to be a decline of 0.05 log10 copies/mL/year, in contrast to recent studies which suggested a reported small increase in viral load over the last 20 years might be due to evolutionary changes in the virus. Our results suggest that in the UK epidemic, subtype B has a small but significant viral genetic effect on viral load. By allowing the analysis of large sample sizes, we expect our approach to be applicable to the estimation of the genetic contribution to traits in many organisms.

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The Contribution of Viral Genotype to Plasma Viral Set-Point in HIV Infection

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