Section: Evolutionary Biology
Topic: Evolution, Health sciences, Genetics/Genomics

Convergent evolution as an indicator for selection during acute HIV-1 infection

10.24072/pcjournal.6 - Peer Community Journal, Volume 1 (2021), article no. e4.

Get full text PDF Peer reviewed and recommended by PCI
Convergent evolution describes the process of different populations acquiring similar phenotypes or genotypes. Complex organisms with large genomes only rarely and only under very strong selection converge to the same genotype. In contrast, independent virus populations with very small genomes often acquire identical mutations. Here we test the hypothesis of whether convergence in early HIV-1 infection is common enough to serve as an indicator for selection. To this end, we measure the number of convergent mutations in a well-studied dataset of full-length HIV-1envgenes sampled from HIV-1 infected individuals during early infection. We compare this data to a neutral model and find an excess of convergent mutations. Convergent mutations are not evenly distributed across the env gene, but more likely to occur in gp41, which suggests that convergent mutations provide a selective advantage and hence are positively selected. In contrast, mutations that are only found in an HIV-1 population of a single individual are significantly affected by purifying selection. Our analysis suggests that comparisons between convergent and private mutations with neutral models allow us to identify positive and negative selection in small viral genomes. Our results also show that selection significantly shapes HIV-1 populations even before the onset of the adaptive immune system.
Published online:
DOI: 10.24072/pcjournal.6
Type: Research article
Bertels, Frederic 1; Metzner, Karin J. 2; Regoes, Roland 3

1 Max Planck Institute for Evolutionary Biology - Plön, Germany
2 University Hospital Zurich, Division of Infectious Disease and Hospital Epidemiology - Zurich, Switzerland
3 Institut für Integrative Biologie, ETH Zurich - Zurich, Switzerland
License: CC-BY 4.0
Copyrights: The authors retain unrestricted copyrights and publishing rights
     author = {Bertels, Frederic and Metzner, Karin J. and Regoes, Roland},
     title = {Convergent evolution as an indicator for selection during acute {HIV-1} infection},
     journal = {Peer Community Journal},
     eid = {e4},
     publisher = {Peer Community In},
     volume = {1},
     year = {2021},
     doi = {10.24072/pcjournal.6},
     url = {}
AU  - Bertels, Frederic
AU  - Metzner, Karin J.
AU  - Regoes, Roland
TI  - Convergent evolution as an indicator for selection during acute HIV-1 infection
JO  - Peer Community Journal
PY  - 2021
VL  - 1
PB  - Peer Community In
UR  -
DO  - 10.24072/pcjournal.6
ID  - 10_24072_pcjournal_6
ER  - 
%0 Journal Article
%A Bertels, Frederic
%A Metzner, Karin J.
%A Regoes, Roland
%T Convergent evolution as an indicator for selection during acute HIV-1 infection
%J Peer Community Journal
%D 2021
%V 1
%I Peer Community In
%R 10.24072/pcjournal.6
%F 10_24072_pcjournal_6
Bertels, Frederic; Metzner, Karin J.; Regoes, Roland. Convergent evolution as an indicator for selection during acute HIV-1 infection. Peer Community Journal, Volume 1 (2021), article  no. e4. doi : 10.24072/pcjournal.6.

PCI peer reviews and recommendation, and links to data, scripts, code and supplementary information: 10.24072/pci.evolbiol.100060

Conflict of interest of the recommender and peer reviewers:
The recommender in charge of the evaluation of the article and the reviewers declared that they have no conflict of interest (as defined in the code of conduct of PCI) with the authors or with the content of the article.

[1] Bertels, F.; Metzner, K.; Regoes, R. Supplementary Data for "Convergent evolution as an indicator for selection during acute HIV-1 infection" (Version 1) [Data set]. Zenodo, (2021) | DOI

[2] Bons, E.; Bertels, F.; Regoes, R. R. Estimating the mutational fitness effects distribution during early HIV infection, Virus Evolution, Volume 4 (2018) no. 2 | DOI

[3] Borrow, P.; Lewicki, H.; Wei, X.; Horwitz, M. S.; Peffer, N.; Meyers, H.; Nelson, J. A.; Gairin, J. E.; Hahn, B. H.; Oldstone, M. B.; Shaw, G. M. Antiviral pressure exerted by HIV-l-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus, Nature Medicine, Volume 3 (1997) no. 2, pp. 205-211 | DOI

[4] Boutwell, C. L.; Rolland, M. M.; Herbeck, J. T.; Mullins, J. I.; Allen, T. M. Viral Evolution and Escape during Acute HIV‐1 Infection, The Journal of Infectious Diseases, Volume 202 (2010) no. S2 | DOI

[5] Bull, J. J.; Badgett, M. R.; Springman, R.; Molineux, I. J. Genome properties and the limits of adaptation in bacteriophages, Evolution, Volume 58 (2004) no. 4, pp. 692-701 | DOI

[6] Carlson, J. M.; Schaefer, M.; Monaco, D. C.; Batorsky, R.; Claiborne, D. T.; Prince, J.; Deymier, M. J.; Ende, Z. S.; Klatt, N. R.; DeZiel, C. E.; Lin, T.-H.; Peng, J.; Seese, A. M.; Shapiro, R.; Frater, J.; Ndung’u, T.; Tang, J.; Goepfert, P.; Gilmour, J.; Price, M. A.; Kilembe, W.; Heckerman, D.; Goulder, P. J. R.; Allen, T. M.; Allen, S.; Hunter, E. Selection bias at the heterosexual HIV-1 transmission bottleneck, Science, Volume 345 (2014) no. 6193, p. 1254031-1254031 | DOI

[7] Chan, D. C.; Fass, D.; Berger, J. M.; Kim, P. S. Core Structure of gp41 from the HIV Envelope Glycoprotein, Cell, Volume 89 (1997) no. 2, pp. 263-273 | DOI

[8] Coffin, J. M. HIV Population Dynamics in Vivo: Implications for Genetic Variation, Pathogenesis, and Therapy, Science, Volume 267 (1995) no. 5197, pp. 483-489 | DOI

[9] Crandall, K. A.; Kelsey, C. R.; Imamichi, H.; Lane, H. C.; Salzman, N. P. Parallel evolution of drug resistance in HIV: failure of nonsynonymous/synonymous substitution rate ratio to detect selection, Molecular Biology and Evolution, Volume 16 (1999) no. 3, pp. 372-382 | DOI

[10] Davey, N. E.; Satagopam, V. P.; Santiago-Mozos, S.; Villacorta-Martin, C.; Bharat, T. A. M.; Schneider, R.; Briggs, J. A. G. The HIV Mutation Browser: A Resource for Human Immunodeficiency Virus Mutagenesis and Polymorphism Data, PLoS Computational Biology, Volume 10 (2014) no. 12 | DOI

[11] Farhat, M. R.; Shapiro, B. J.; Kieser, K. J.; Sultana, R.; Jacobson, K. R.; Victor, T. C.; Warren, R. M.; Streicher, E. M.; Calver, A.; Sloutsky, A.; Kaur, D.; Posey, J. E.; Plikaytis, B.; Oggioni, M. R.; Gardy, J. L.; Johnston, J. C.; Rodrigues, M.; Tang, P. K. C.; Kato-Maeda, M.; Borowsky, M. L.; Muddukrishna, B.; Kreiswirth, B. N.; Kurepina, N.; Galagan, J.; Gagneux, S.; Birren, B.; Rubin, E. J.; Lander, E. S.; Sabeti, P. C.; Murray, M. Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis, Nature Genetics, Volume 45 (2013) no. 10, pp. 1183-1189 | DOI

[12] Foley, B.; Leitner, T.; Apetrei, C.; Hahn, B. HIV sequence compendium 2013. Los Alamos., (2013)

[13] Foll, M.; Poh, Y.-P.; Renzette, N.; Ferrer-Admetlla, A.; Bank, C.; Shim, H.; Malaspinas, A.-S.; Ewing, G.; Liu, P.; Wegmann, D.; Caffrey, D. R.; Zeldovich, K. B.; Bolon, D. N.; Wang, J. P.; Kowalik, T. F.; Schiffer, C. A.; Finberg, R. W.; Jensen, J. D. Influenza Virus Drug Resistance: A Time-Sampled Population Genetics Perspective, PLoS Genetics, Volume 10 (2014) no. 2 | DOI

[14] Garcia-Knight, M. A.; Slyker, J.; Payne, B. L.; Pond, S. L. K.; de Silva, T. I.; Chohan, B.; Khasimwa, B.; Mbori-Ngacha, D.; John-Stewart, G.; Rowland-Jones, S. L.; Esbjörnsson, J. Viral Evolution and Cytotoxic T Cell Restricted Selection in Acute Infant HIV-1 Infection, Scientific Reports, Volume 6 (2016) no. 1 | DOI

[15] Giorgi, E. E.; Korber, B. T.; Perelson, A. S.; Bhattacharya, T. Modeling sequence evolution in HIV-1 infection with recombination, Journal of Theoretical Biology, Volume 329 (2013), pp. 82-93 | DOI

[16] Goulder, P. J.; Phillips, R. E.; Colbert, R. A.; McAdam, S.; Ogg, G.; Nowak, M. A.; Giangrande, P.; Luzzi, G.; Morgana, B.; Edwards, A.; McMichael, A. J.; Rowland-Jones, S. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS, Nature Medicine, Volume 3 (1997) no. 2, pp. 212-217 | DOI

[17] Henn, M. R.; Boutwell, C. L.; Charlebois, P.; Lennon, N. J.; Power, K. A.; Macalalad, A. R.; Berlin, A. M.; Malboeuf, C. M.; Ryan, E. M.; Gnerre, S.; Zody, M. C.; Erlich, R. L.; Green, L. M.; Berical, A.; Wang, Y.; Casali, M.; Streeck, H.; Bloom, A. K.; Dudek, T.; Tully, D.; Newman, R.; Axten, K. L.; Gladden, A. D.; Battis, L.; Kemper, M.; Zeng, Q.; Shea, T. P.; Gujja, S.; Zedlack, C.; Gasser, O.; Brander, C.; Hess, C.; Günthard, H. F.; Brumme, Z. L.; Brumme, C. J.; Bazner, S.; Rychert, J.; Tinsley, J. P.; Mayer, K. H.; Rosenberg, E.; Pereyra, F.; Levin, J. Z.; Young, S. K.; Jessen, H.; Altfeld, M.; Birren, B. W.; Walker, B. D.; Allen, T. M. Whole Genome Deep Sequencing of HIV-1 Reveals the Impact of Early Minor Variants Upon Immune Recognition During Acute Infection, PLoS Pathogens, Volume 8 (2012) no. 3 | DOI

[18] Herbeck, J. T.; Rolland, M.; Liu, Y.; McLaughlin, S.; McNevin, J.; Zhao, H.; Wong, K.; Stoddard, J. N.; Raugi, D.; Sorensen, S.; Genowati, I.; Birditt, B.; McKay, A.; Diem, K.; Maust, B. S.; Deng, W.; Collier, A. C.; Stekler, J. D.; McElrath, M. J.; Mullins, J. I. Demographic Processes Affect HIV-1 Evolution in Primary Infection before the Onset of Selective Processes, Journal of Virology, Volume 85 (2011) no. 15, pp. 7523-7534 | DOI

[19] Ince, W. L.; Zhang, L.; Jiang, Q.; Arrildt, K.; Su, L.; Swanstrom, R. Evolution of the HIV-1 env Gene in the Rag2 −/− γ C −/− Humanized Mouse Model, Journal of Virology, Volume 84 (2010) no. 6, pp. 2740-2752 | DOI

[20] Keele, B. F.; Giorgi, E. E.; Salazar-Gonzalez, J. F.; Decker, J. M.; Pham, K. T.; Salazar, M. G.; Sun, C.; Grayson, T.; Wang, S.; Li, H.; Wei, X.; Jiang, C.; Kirchherr, J. L.; Gao, F.; Anderson, J. A.; Ping, L.-H.; Swanstrom, R.; Tomaras, G. D.; Blattner, W. A.; Goepfert, P. A.; Kilby, J. M.; Saag, M. S.; Delwart, E. L.; Busch, M. P.; Cohen, M. S.; Montefiori, D. C.; Haynes, B. F.; Gaschen, B.; Athreya, G. S.; Lee, H. Y.; Wood, N.; Seoighe, C.; Perelson, A. S.; Bhattacharya, T.; Korber, B. T.; Hahn, B. H.; Shaw, G. M. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection, Proceedings of the National Academy of Sciences, Volume 105 (2008) no. 21, pp. 7552-7557 | DOI

[21] Koenig, S.; Conley, A. J.; Brewah, Y. A.; Jones, G. M.; Leath, S.; Boots, L. J.; Davey, V.; Pantaleo, G.; Demarest, J. F.; Carter, C.; Wannebo, C.; Yannelli, J. R.; Rosenberg, S. A.; Lane, H. C. Transfer of HIV-1-specific cytotoxic T lymphocytes to an AIDS patient leads to selection for mutant HIV variants and subsequent disease progression, Nature Medicine, Volume 1 (1995) no. 4, pp. 330-336 | DOI

[22] Kosakovsky Pond, S. L.; Poon, A. F. Y.; Zárate, S.; Smith, D. M.; Little, S. J.; Pillai, S. K.; Ellis, R. J.; Wong, J. K.; Leigh Brown, A. J.; Richman, D. D.; Frost, S. D. W. Estimating selection pressures on HIV-1 using phylogenetic likelihood models, Statistics in Medicine, Volume 27 (2008) no. 23, pp. 4779-4789 | DOI

[23] Lee, H. Y.; Giorgi, E. E.; Keele, B. F.; Gaschen, B.; Athreya, G. S.; Salazar-Gonzalez, J. F.; Pham, K. T.; Goepfert, P. A.; Michael Kilby, J.; Saag, M. S.; Delwart, E. L.; Busch, M. P.; Hahn, B. H.; Shaw, G. M.; Korber, B. T.; Bhattacharya, T.; Perelson, A. S. Modeling sequence evolution in acute HIV-1 infection, Journal of Theoretical Biology, Volume 261 (2009) no. 2, pp. 341-360 | DOI

[24] Lemey, P.; Rambaut, A.; Pybus, O. HIV evolutionary dynamics within and among hosts, AIDS reviews, Volume 8 (2006), pp. 125-140

[25] Li, H.; Bar, K. J.; Wang, S.; Decker, J. M.; Chen, Y.; Sun, C.; Salazar-Gonzalez, J. F.; Salazar, M. G.; Learn, G. H.; Morgan, C. J.; Schumacher, J. E.; Hraber, P.; Giorgi, E. E.; Bhattacharya, T.; Korber, B. T.; Perelson, A. S.; Eron, J. J.; Cohen, M. S.; Hicks, C. B.; Haynes, B. F.; Markowitz, M.; Keele, B. F.; Hahn, B. H.; Shaw, G. M. High Multiplicity Infection by HIV-1 in Men Who Have Sex with Men, PLoS Pathogens, Volume 6 (2010) no. 5 | DOI

[26] Liao, H.-X.; Lynch, R.; Zhou, T.; Gao, F.; Alam, S. M.; Boyd, S. D.; Fire, A. Z.; Roskin, K. M.; Schramm, C. A.; Zhang, Z.; Zhu, J.; Shapiro, L.; Mullikin, J. C.; Gnanakaran, S.; Hraber, P.; Wiehe, K.; Kelsoe, G.; Yang, G.; Xia, S.-M.; Montefiori, D. C.; Parks, R.; Lloyd, K. E.; Scearce, R. M.; Soderberg, K. A.; Cohen, M.; Kamanga, G.; Louder, M. K.; Tran, L. M.; Chen, Y.; Cai, F.; Chen, S.; Moquin, S.; Du, X.; Joyce, M. G.; Srivatsan, S.; Zhang, B.; Zheng, A.; Shaw, G. M.; Hahn, B. H.; Kepler, T. B.; Korber, B. T. M.; Kwong, P. D.; Mascola, J. R.; Haynes, B. F. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus, Nature, Volume 496 (2013) no. 7446, pp. 469-476 | DOI

[27] Lindsey, H. A.; Gallie, J.; Taylor, S.; Kerr, B. Evolutionary rescue from extinction is contingent on a lower rate of environmental change, Nature, Volume 494 (2013) no. 7438, pp. 463-467 | DOI

[28] Mansky, L. M. Forward Mutation Rate of Human Immunodeficiency Virus Type 1 in a T Lymphoid Cell Line*, AIDS Research and Human Retroviruses, Volume 12 (1996) no. 4, pp. 307-314 | DOI

[29] Melikyan, G. B.; Markosyan, R. M.; Hemmati, H.; Delmedico, M. K.; Lambert, D. M.; Cohen, F. S. Evidence That the Transition of HIV-1 Gp41 into a Six-Helix Bundle, Not the Bundle Configuration, Induces Membrane Fusion, Journal of Cell Biology, Volume 151 (2000) no. 2, pp. 413-424 | DOI

[30] Miki, Y.; Swensen, J.; Shattuck-Eidens, D.; Futreal, P. A.; Harshman, K.; Tavtigian, S.; Liu, Q.; Cochran, C.; Bennett, L. M.; Ding, W.; Bell, R.; Rosenthal, J.; Hussey, C.; Tran, T.; McClure, M.; Frye, C.; Hattier, T.; Phelps, R.; Haugen-Strano, A.; Katcher, H.; Yakumo, K.; Gholami, Z.; Shaffer, D.; Stone, S.; Bayer, S.; Wray, C.; Bogden, R.; Dayananth, P.; Ward, J.; Tonin, P.; Narod, S.; Bristow, P. K.; Norris, F. H.; Helvering, L.; Morrison, P.; Rosteck, P.; Lai, M.; Barrett, J. C.; Lewis, C.; Neuhausen, S.; Cannon-Albright, L.; Goldgar, D.; Wiseman, R.; Kamb, A.; Skolnick, M. H. A Strong Candidate for the Breast and Ovarian Cancer Susceptibility Gene BRCA1, Science, Volume 266 (1994) no. 5182, pp. 66-71 | DOI

[31] O'Rourke, S. M.; Schweighardt, B.; Phung, P.; Mesa, K. A.; Vollrath, A. L.; Tatsuno, G. P.; To, B.; Sinangil, F.; Limoli, K.; Wrin, T.; Berman, P. W. Sequences in Glycoprotein gp41, the CD4 Binding Site, and the V2 Domain Regulate Sensitivity and Resistance of HIV-1 to Broadly Neutralizing Antibodies, Journal of Virology, Volume 86 (2012) no. 22, pp. 12105-12114 | DOI

[32] Park, S. Y.; Love, T. M. T.; Perelson, A. S.; Mack, W. J.; Lee, H. Y. Molecular clock of HIV-1 envelope genes under early immune selection, Retrovirology, Volume 13 (2016) no. 1 | DOI

[33] Poon, A. F.; Swenson, L. C.; Dong, W. W.; Deng, W.; Kosakovsky Pond, S. L.; Brumme, Z. L.; Mullins, J. I.; Richman, D. D.; Harrigan, P. R.; Frost, S. D. Phylogenetic Analysis of Population-Based and Deep Sequencing Data to Identify Coevolving Sites in the nef Gene of HIV-1, Molecular Biology and Evolution, Volume 27 (2010) no. 4, pp. 819-832 | DOI

[34] Serb, J. M.; Eernisse, D. J. Charting Evolution’s Trajectory: Using Molluscan Eye Diversity to Understand Parallel and Convergent Evolution, Evolution: Education and Outreach, Volume 1 (2008) no. 4, pp. 439-447 | DOI

[35] Shankarappa, R.; Margolick, J. B.; Gange, S. J.; Rodrigo, A. G.; Upchurch, D.; Farzadegan, H.; Gupta, P.; Rinaldo, C. R.; Learn, G. H.; He, X.; Huang, X.-L.; Mullins, J. I. Consistent Viral Evolutionary Changes Associated with the Progression of Human Immunodeficiency Virus Type 1 Infection, Journal of Virology, Volume 73 (1999) no. 12, pp. 10489-10502 | DOI

[36] Sievers, F.; Wilm, A.; Dineen, D.; Gibson, T. J.; Karplus, K.; Li, W.; Lopez, R.; McWilliam, H.; Remmert, M.; Söding, J.; Thompson, J. D.; Higgins, D. G. Fast, scalable generation of high‐quality protein multiple sequence alignments using Clustal Omega, Molecular Systems Biology, Volume 7 (2011) no. 1 | DOI

[37] Skehel, J. J.; Wiley, D. C. Coiled Coils in Both Intracellular Vesicle and Viral Membrane Fusion, Cell, Volume 95 (1998) no. 7, pp. 871-874 | DOI

[38] Stayton, C. T. What does convergent evolution mean? The interpretation of convergence and its implications in the search for limits to evolution, Interface Focus, Volume 5 (2015) no. 6 | DOI

[39] Team RC. R: A Language and Environment for Statistical Computing. Available from:

[40] Trkola, A.; Kuster, H.; Rusert, P.; Joos, B.; Fischer, M.; Leemann, C.; Manrique, A.; Huber, M.; Rehr, M.; Oxenius, A.; Weber, R.; Stiegler, G.; Vcelar, B.; Katinger, H.; Aceto, L.; Günthard, H. F. Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive transfer of human neutralizing antibodies, Nature Medicine, Volume 11 (2005) no. 6, pp. 615-622 | DOI

[41] Wei, X.; Decker, J. M.; Wang, S.; Hui, H.; Kappes, J. C.; Wu, X.; Salazar-Gonzalez, J. F.; Salazar, M. G.; Kilby, J. M.; Saag, M. S.; Komarova, N. L.; Nowak, M. A.; Hahn, B. H.; Kwong, P. D.; Shaw, G. M. Antibody neutralization and escape by HIV-1, Nature, Volume 422 (2003) no. 6929, pp. 307-312 | DOI

[42] Wichman, H. A.; Scott, L. A.; Yarber, C. D.; Bull, J. J. Experimental evolution recapitulates natural evolution, Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, Volume 355 (2000) no. 1403, pp. 1677-1684 | DOI

[43] Wickham, H. ggplot2, Use R!, Springer International Publishing, Cham | DOI

[44] Wilke, C. Streamlined Plot Theme and Plot Annotations for “ggplot2” [R package cowplot version 0.8.0]. Available from:, (2016)

[45] Wood, N.; Bhattacharya, T.; Keele, B. F.; Giorgi, E.; Liu, M.; Gaschen, B.; Daniels, M.; Ferrari, G.; Haynes, B. F.; McMichael, A.; Shaw, G. M.; Hahn, B. H.; Korber, B.; Seoighe, C. HIV Evolution in Early Infection: Selection Pressures, Patterns of Insertion and Deletion, and the Impact of APOBEC, PLoS Pathogens, Volume 5 (2009) no. 5 | DOI

[46] Xue, K. S.; Stevens-Ayers, T.; Campbell, A. P.; Englund, J. A.; Pergam, S. A.; Boeckh, M.; Bloom, J. D. Parallel evolution of influenza across multiple spatiotemporal scales, eLife, Volume 6 (2017) | DOI

[47] Yoshida, I.; Sugiura, W.; Shibata, J.; Ren, F.; Yang, Z.; Tanaka, H. Change of Positive Selection Pressure on HIV-1 Envelope Gene Inferred by Early and Recent Samples, PLoS ONE, Volume 6 (2011) no. 4 | DOI

[48] Zhang, Z.; Townsend, J. P. Maximum-Likelihood Model Averaging To Profile Clustering of Site Types across Discrete Linear Sequences, PLoS Computational Biology, Volume 5 (2009) no. 6 | DOI

[49] Zhao, Z.-M.; Campbell, M. C.; Li, N.; Lee, D. S.; Zhang, Z.; Townsend, J. P. Detection of Regional Variation in Selection Intensity within Protein-Coding Genes Using DNA Sequence Polymorphism and Divergence, Molecular Biology and Evolution, Volume 34 (2017) no. 11, pp. 3006-3022 | DOI

Cited by Sources: