Distinct rates and patterns of spread of the major HIV-1 subtypes in Central and East Africa

English version

Autoři: Nuno R. Faria ^aff001; Nicole Vidal ^aff002; José Lourenco ^aff001; Jayna Raghwani ^aff001; Kim C. E. Sigaloff ^aff003; Andy J. Tatem ^aff005; David A. M. van de Vijver ^aff007; Andrea-Clemencia Pineda-Peña ^aff008; Rebecca Rose ^aff010; Carole L. Wallis ^aff011; Steve Ahuka-Mundeke ^aff012; Jean-Jacques Muyembe-Tamfum ^aff012; Jérémie Muwonga ^aff013; Marc A. Suchard ^aff014; Tobias F. Rinke de Wit ^aff003; Raph L. Hamers ^aff003; Nicaise Ndembi ^aff015; Guy Baele ^aff016; Martine Peeters ^aff002; Oliver G. Pybus ^aff001; Philippe Lemey ^aff016; Simon Dellicour ^aff016
Působiště autorů: Department of Zoology, University of Oxford, Oxford, United Kingdom ^aff001; TransVIHMI, Institut de Recherche pour le Développement, INSERM, and University of Montpellier, Montpellier, France ^aff002; Amsterdam Institute for Global Health and Development, Department of Global Health, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands ^aff003; Department of Internal Medicine, Section of Infectious Diseases, VU University Medical Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands ^aff004; Department of Geography and Environment, University of Southampton, Southampton, United Kingdom ^aff005; Flowminder Foundation, Stockholm, Sweden ^aff006; Viroscience Department, Erasmus Medical Center, Rotterdam, The Netherlands ^aff007; Global Health and Tropical Medicine—Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisboa, Portugal ^aff008; Molecular Biology and Immunology Department, Fundación Instituto de Inmunología de Colombia, Basic Sciences Department, Universidad del Rosario, Bogotá, Colombia ^aff009; Bioinfoexperts, LLC, Thibodaux, Los Angeles, United States of America ^aff010; Department of Molecular Pathology, Lancet Laboratories and BARC-SA, Johannesburg, South Africa ^aff011; Institut National de Recherche Biomedicales, Kinshasa, Democratic Republic of Congo and Service de Microbiologie, Cliniques Universitaires de Kinshasa, Kinshasa, Democratic Republic of Congo ^aff012; AIDS national laboratory and Service de Microbiologie, Cliniques Universitaires de Kinshasa, Kinshasa, Democratic Republic of Congo ^aff013; Departments of Biomathematics and Human Genetics David Geffen School of Medicine at UCLA, and Department of Biostatistics UCLA School of Public Health, Los Angeles, United States of America ^aff014; Institute of Human Virology, Abuja, Nigeria ^aff015; KU Leuven, Department of Microbiology and Immunology, Rega Institute, Laboratory for Clinical and Epidemiological Virology, Leuven, Belgium ^aff016; Spatial Epidemiology Lab, Université Libre de Bruxelles, Bruxels, Belgium ^aff017
Vyšlo v časopise: Distinct rates and patterns of spread of the major HIV-1 subtypes in Central and East Africa. PLoS Pathog 15(12): e32767. doi:10.1371/journal.ppat.1007976
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1007976

Souhrn

Since the ignition of the HIV-1 group M pandemic in the beginning of the 20th century, group M lineages have spread heterogeneously throughout the world. Subtype C spread rapidly through sub-Saharan Africa and is currently the dominant HIV lineage worldwide. Yet the epidemiological and evolutionary circumstances that contributed to its epidemiological expansion remain poorly understood. Here, we analyse 346 novel pol sequences from the DRC to compare the evolutionary dynamics of the main HIV-1 lineages, subtypes A1, C and D. Our results place the origins of subtype C in the 1950s in Mbuji-Mayi, the mining city of southern DRC, while subtypes A1 and D emerged in the capital city of Kinshasa, and subtypes H and J in the less accessible port city of Matadi. Following a 15-year period of local transmission in southern DRC, we find that subtype C spread at least three-fold faster than other subtypes circulating in Central and East Africa. In conclusion, our results shed light on the origins of HIV-1 main lineages and suggest that socio-historical rather than evolutionary factors may have determined the epidemiological fate of subtype C in sub-Saharan Africa.

Klíčová slova:

Africa – HIV epidemiology – HIV-1 – Phylogenetic analysis – Phylogenetics – Phylogeography – Sequence analysis – Uganda

Zdroje

1. UNAIDS. Global AIDS update 2019. 2019.

2. Faria NR, Rambaut A, Suchard MA, Baele G, Bedford T, Ward MJ, et al. HIV epidemiology. The early spread and epidemic ignition of HIV-1 in human populations. Science. 2014;346(6205):56–61. Epub 2014/10/04. doi: 10.1126/science.1256739 25278604.

3. Korber B, Muldoon M, Theiler J, Gao F, Gupta R, Lapedes A, et al. Timing the ancestor of the HIV-1 pandemic strains. Science. 2000;288(5472):1789–96. doi: 10.1126/science.288.5472.1789 10846155.

4. Worobey M, Gemmel M, Teuwen DE, Haselkorn T, Kunstman K, Bunce M, et al. Direct evidence of extensive diversity of HIV-1 in Kinshasa by 1960. Nature. 2008;455(7213):661–4. doi: 10.1038/nature07390 18833279; PubMed Central PMCID: PMC3682493.

5. Zhu T, Korber BT, Nahmias AJ, Hooper E, Sharp PM, Ho DD. An African HIV-1 sequence from 1959 and implications for the origin of the epidemic. Nature. 1998;391(6667):594–7. doi: 10.1038/35400 9468138.

6. Rambaut A, Robertson DL, Pybus OG, Peeters M, Holmes EC. Human immunodeficiency virus. Phylogeny and the origin of HIV-1. Nature. 2001;410(6832):1047–8. doi: 10.1038/35074179 11323659.

7. HIV Los Alamos sequence database [Internet]. 2016. Available from: http://www.hiv.lanl.gov/.

8. Bartolo I, Calado R, Borrego P, Leitner T, Taveira N. Rare HIV-1 Subtype J Genomes and a New H/U/CRF02_AG Recombinant Genome Suggests an Ancient Origin of HIV-1 in Angola. AIDS research and human retroviruses. 2016. doi: 10.1089/AID.2016.0084 27098898.

9. Bartolo I, Rocha C, Bartolomeu J, Gama A, Marcelino R, Fonseca M, et al. Highly divergent subtypes and new recombinant forms prevail in the HIV/AIDS epidemic in Angola: new insights into the origins of the AIDS pandemic. Infection, Genetics and Evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases. 2009;9(4):672–82. doi: 10.1016/j.meegid.2008.05.003 18562253.

10. Kalish ML, Robbins KE, Pieniazek D, Schaefer A, Nzilambi N, Quinn TC, et al. Recombinant viruses and early global HIV-1 epidemic. Emerging Infectious Diseases. 2004;10(7):1227–34. doi: 10.3201/eid1007.030904 15324542; PubMed Central PMCID: PMC3323344.

11. Gray RR, Tatem AJ, Lamers S, Hou W, Laeyendecker O, Serwadda D, et al. Spatial phylodynamics of HIV-1 epidemic emergence in east Africa. AIDS. 2009;23(14):F9–F17. Epub 2009/08/01. doi: 10.1097/QAD.0b013e32832faf61 19644346; PubMed Central PMCID: PMC2742553.

12. Hemelaar J, Gouws E, Ghys PD, Osmanov S, Isolation W-UNfH, Characterisation. Global trends in molecular epidemiology of HIV-1 during 2000–2007. AIDS. 2011;25(5):679–89. doi: 10.1097/QAD.0b013e328342ff93 21297424; PubMed Central PMCID: PMC3755761.

13. Hemelaar J, Elangovan R, Yun J, Dickson-Tetteh L, Fleminger I, Kirtley S, et al. Global and regional molecular epidemiology of HIV-1, 1990–2015: a systematic review, global survey, and trend analysis. The Lancet infectious diseases. 2019;19(2):143–55. Epub 2018/12/05. doi: 10.1016/S1473-3099(18)30647-9 30509777.

14. Tatem AJ, Hemelaar J, Gray RR, Salemi M. Spatial accessibility and the spread of HIV-1 subtypes and recombinants. AIDS. 2012;26(18):2351–60. doi: 10.1097/QAD.0b013e328359a904 22951637.

15. Weine SM, Kashuba AB. Labor migration and HIV risk: a systematic review of the literature. AIDS and behavior. 2012;16(6):1605–21. Epub 2012/04/07. doi: 10.1007/s10461-012-0183-4 22481273; PubMed Central PMCID: PMC3780780.

16. Chitnis A, Rawls D, Moore J. Origin of HIV type 1 in colonial French Equatorial Africa? AIDS research and human retroviruses. 2000;16(1):5–8. doi: 10.1089/088922200309548 10628811.

17. Giles-Vernick T, Gondola CD, Lachenal G, Schneider WH. Social History, Biology, and the Emergence of Hiv in Colonial Africa. J Afr Hist. 2013;54(1):11–30. doi: 10.1017/S0021853713000029 WOS:000318916600002.

18. Pepin J. The origins of AIDS: from patient zero to ground zero. J Epidemiol Commun H. 2013;67(6):473–5. doi: 10.1136/jech-2012-201423 WOS:000318490600003. 23322854

19. Arien KK, Abraha A, Quinones-Mateu ME, Kestens L, Vanham G, Arts EJ. The replicative fitness of primary human immunodeficiency virus type 1 (HIV-1) group M, HIV-1 group O, and HIV-2 isolates. Journal of virology. 2005;79(14):8979–90. Epub 2005/07/05. doi: 10.1128/JVI.79.14.8979-8990.2005 15994792; PubMed Central PMCID: PMC1168791.

20. Vidal N, Mulanga C, Bazepeo SE, Mwamba JK, Tshimpaka JW, Kashi M, et al. Distribution of HIV-1 variants in the Democratic Republic of Congo suggests increase of subtype C in Kinshasa between 1997 and 2002. Journal of acquired immune deficiency syndromes. 2005;40(4):456–62. Epub 2005/11/11. doi: 10.1097/01.qai.0000159670.18326.94 16280702.

21. Wilkinson E, Engelbrecht S, de Oliveira T. History and origin of the HIV-1 subtype C epidemic in South Africa and the greater southern African region. Scientific reports. 2015;5:16897. doi: 10.1038/srep16897 26574165; PubMed Central PMCID: PMC4648088.

22. Delatorre EO, Bello G. Phylodynamics of HIV-1 subtype C epidemic in east Africa. PloS one. 2012;7(7):e41904. doi: 10.1371/journal.pone.0041904 22848653; PubMed Central PMCID: PMC3407063.

23. Wilkinson E, Rasmussen D, Ratmann O, Stadler T, Engelbrecht S, de Oliveira T. Origin, imports and exports of HIV-1 subtype C in South Africa: A historical perspective. Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases. 2016. doi: 10.1016/j.meegid.2016.07.008 27421210.

24. Yebra G, Ragonnet-Cronin M, Ssemwanga D, Parry CM, Logue CH, Cane PA, et al. Analysis of the history and spread of HIV-1 in Uganda using phylodynamics. The Journal of general virology. 2015;96(7):1890–8. Epub 2015/03/01. doi: 10.1099/vir.0.000107 25724670.

25. Dellicour S, Vrancken B, Trovao NS, Fargette D, Lemey P. On the importance of negative controls in viral landscape phylogeography. Virus Evol. 2018;4(2):vey023. Epub 2018/08/29. doi: 10.1093/ve/vey023 30151241; PubMed Central PMCID: PMC6101606.

26. Lemey P, Rambaut A, Drummond AJ, Suchard MA. Bayesian phylogeography finds its roots. PLoS computational biology. 2009;5(9):e1000520. doi: 10.1371/journal.pcbi.1000520 19779555; PubMed Central PMCID: PMC2740835.

27. Lihana RW, Ssemwanga D, Abimiku A, Ndembi N. Update on HIV-1 diversity in Africa: a decade in review. AIDS reviews. 2012;14(2):83–100. Epub 2012/05/26. 22627605.

28. Huybrechts A. Transports et structures de development au Congo: etude du progres economique de 1900–1970: Paris: Mouton; 1970.

29. Villabona Arenas CJ, Vidal N, Ahuka Mundeke S, Muwonga J, Serrano L, Muyembe JJ, et al. Divergent HIV-1 strains (CRF92_C2U and CRF93_cpx) co-circulating in the Democratic Republic of the Congo: Phylogenetic insights on the early evolutionary history of subtype C. Virus Evol. 2017;3(2):vex032. Epub 2017/12/19. doi: 10.1093/ve/vex032 29250430; PubMed Central PMCID: PMC5724398.

30. Cybis GB, Sinsheimer JS, Lemey P, Suchard MA. Graph hierarchies for phylogeography. Philos Trans R Soc Lond B Biol Sci. 2013;368(1614):20120206. Epub 2013/02/06. doi: 10.1098/rstb.2012.0206 23382428; PubMed Central PMCID: PMC3678330.

31. Lemey P, Minin VN, Bielejec F, Kosakovsky Pond SL, Suchard MA. A counting renaissance: combining stochastic mapping and empirical Bayes to quickly detect amino acid sites under positive selection. Bioinformatics. 2012;28(24):3248–56. Epub 2012/10/16. doi: 10.1093/bioinformatics/bts580 23064000; PubMed Central PMCID: PMC3579240.

32. Minin VN, Suchard MA. Counting labeled transitions in continuous-time Markov models of evolution. Journal of mathematical biology. 2008;56(3):391–412. doi: 10.1007/s00285-007-0120-8 17874105.

33. Minin VN, Suchard MA. Fast, accurate and simulation-free stochastic mapping. Philos Trans R Soc Lond B Biol Sci. 2008;363(1512):3985–95. doi: 10.1098/rstb.2008.0176 18852111; PubMed Central PMCID: PMC2607419.

34. O'Brien JD, Minin V. N., Suchard M. A. Learning to count: robust estimates for labeled distances between molecular sequences. Molecular biology and evolution. 2009;26(4):801–14. doi: 10.1093/molbev/msp003 19131426

35. Faria NR, Suchard MA, Abecasis A, Sousa JD, Ndembi N, Bonfim I, et al. Phylodynamics of the HIV-1 CRF02_AG clade in Cameroon. Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases. 2012;12(2):453–60. Epub 2011/05/14. doi: 10.1016/j.meegid.2011.04.028 21565285.

36. Faria NR, Suchard MA, Rambaut A, Lemey P. Toward a quantitative understanding of viral phylogeography. Current opinion in virology. 2011;1(5):423–9. Epub 2012/03/24. doi: 10.1016/j.coviro.2011.10.003 22440846; PubMed Central PMCID: PMC3312803.

37. Talbi C, Lemey P, Suchard MA, Abdelatif E, Elharrak M, Nourlil J, et al. Phylodynamics and human-mediated dispersal of a zoonotic virus. PLoS pathogens. 2010;6(10):e1001166. doi: 10.1371/journal.ppat.1001166 21060816; PubMed Central PMCID: PMC2965766.

38. Stadler T, Kouyos R, von Wyl V, Yerly S, Boni J, Burgisser P, et al. Estimating the basic reproductive number from viral sequence data. Molecular biology and evolution. 2012;29(1):347–57. Epub 2011/09/06. doi: 10.1093/molbev/msr217 21890480.

39. Iversen AK, Learn GH, Skinhoj P, Mullins JI, McMichael AJ, Rambaut A. Preferential detection of HIV subtype C' over subtype A in cervical cells from a dually infected woman. AIDS. 2005;19(9):990–3. Epub 2005/05/21. doi: 10.1097/01.aids.0000171418.91786.ad 15905685.

40. Kiwanuka N, Laeyendecker O, Quinn TC, Wawer MJ, Shepherd J, Robb M, et al. HIV-1 subtypes and differences in heterosexual HIV transmission among HIV-discordant couples in Rakai, Uganda. Aids. 2009;23(18):2479–84. Epub 2009/10/21. doi: 10.1097/QAD.0b013e328330cc08 19841572; PubMed Central PMCID: PMC2910931.

41. Arien KK, Vanham G, Arts EJ. Is HIV-1 evolving to a less virulent form in humans? Nature reviews Microbiology. 2007;5(2):141–51. Epub 2007/01/05. doi: 10.1038/nrmicro1594 17203103.

42. Kuhnert D, Stadler T, Vaughan TG, Drummond AJ. Phylodynamics with Migration: A Computational Framework to Quantify Population Structure from Genomic Data. Molecular biology and evolution. 2016;33(8):2102–16. Epub 2016/05/18. doi: 10.1093/molbev/msw064 27189573; PubMed Central PMCID: PMC4948704.

43. Stadler T, Vaughan TG, Gavryushkin A, Guindon S, Kuhnert D, Leventhal GE, et al. How well can the exponential-growth coalescent approximate constant-rate birth-death population dynamics? Proceedings Biological sciences / The Royal Society. 2015;282(1806):20150420. Epub 2015/04/17. doi: 10.1098/rspb.2015.0420 25876846; PubMed Central PMCID: PMC4426635.

44. Fraser C, Hollingsworth TD, Chapman R, de Wolf F, Hanage WP. Variation in HIV-1 set-point viral load: epidemiological analysis and an evolutionary hypothesis. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(44):17441–6. Epub 2007/10/24. doi: 10.1073/pnas.0708559104 17954909; PubMed Central PMCID: PMC2077275.

45. Seibert SA, Howell CY, Hughes MK, Hughes AL. Natural selection on the gag, pol, and env genes of human immunodeficiency virus 1 (HIV-1). Molecular biology and evolution. 1995;12(5):803–13. Epub 1995/09/01. doi: 10.1093/oxfordjournals.molbev.a040257 7476126.

46. Abecasis A, Paraskevis D, Epalanga M, Fonseca M, Burity F, Bartolomeu J, et al. HIV-1 genetic variants circulation in the North of Angola. Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases. 2005;5(3):231–7. doi: 10.1016/j.meegid.2004.07.007 15737914.

47. Hogan C, Iles J, Frost EH, Giroux G, Cassar O, Gessain A, et al. Epidemic history and iatrogenic transmission of blood-borne viruses in mid-20th century Kinshasa. The Journal of infectious diseases. 2016. doi: 10.1093/infdis/jiw009 26768251.

48. Hazlewood A Rail and road in East Africa; transport co-ordination in under-developed countries. Oxford,: B. Blackwell; 1964. xiii, 247 p. p.

49. Bwayo J, Plummer F, Omari M, Mutere A, Moses S, Ndinya-Achola J, et al. Human immunodeficiency virus infection in long-distance truck drivers in east Africa. Archives of internal medicine. 1994;154(12):1391–6. Epub 1994/06/27. 8002691.

50. Mbugua GG, Muthami LN, Mutura CW, Oogo SA, Waiyaki PG, Lindan CP, et al. Epidemiology of HIV infection among long distance truck drivers in Kenya. East African medical journal. 1995;72(8):515–8. Epub 1995/08/01. 7588147.

51. Nzyuko S, Lurie P, McFarland W, Leyden W, Nyamwaya D, Mandel JS. Adolescent sexual behavior along the Trans-Africa Highway in Kenya. AIDS. 1997;11 Suppl 1:S21–6. Epub 1997/10/31. 9376097.

52. Vidal N, Peeters M, Mulanga-Kabeya C, Nzilambi N, Robertson D, Ilunga W, et al. Unprecedented degree of human immunodeficiency virus type 1 (HIV-1) group M genetic diversity in the Democratic Republic of Congo suggests that the HIV-1 pandemic originated in Central Africa. Journal of virology. 2000;74(22):10498–507. doi: 10.1128/jvi.74.22.10498-10507.2000 11044094; PubMed Central PMCID: PMC110924.

53. Abecasis AB, Lemey P, Vidal N, de Oliveira T, Peeters M, Camacho R, et al. Recombination confounds the early evolutionary history of human immunodeficiency virus type 1: subtype G is a circulating recombinant form. Journal of virology. 2007;81(16):8543–51. doi: 10.1128/JVI.00463-07 17553886; PubMed Central PMCID: PMC1951349.

54. Tee KK, Pybus OG, Parker J, Ng KP, Kamarulzaman A, Takebe Y. Estimating the date of origin of an HIV-1 circulating recombinant form. Virology. 2009;387(1):229–34. doi: 10.1016/j.virol.2009.02.020 19272628.

55. Delatorre E, Bello G. Phylodynamics of the HIV-1 epidemic in Cuba. PloS one. 2013;8(9):e72448. doi: 10.1371/journal.pone.0072448 24039765; PubMed Central PMCID: PMC3767668.

56. Delatorre E, Couto-Fernandez JC, Guimaraes ML, Vaz Cardoso LP, de Alcantara KC, Stefani MM, et al. Tracing the origin and northward dissemination dynamics of HIV-1 subtype C in Brazil. PloS one. 2013;8(9):e74072. doi: 10.1371/journal.pone.0074072 24069269; PubMed Central PMCID: PMC3771961.

57. Delatorre E, Mir D, Bello G. Spatiotemporal Dynamics of the HIV-1 Subtype G Epidemic in West and Central Africa. PloS one. 2014;9(2):e98908. doi: 10.1371/journal.pone.0098908 24918930; PubMed Central PMCID: PMC4053352.

58. Faria NR, Lourenco J., Cerqueira E. M., Lima M. M., Pybus O. G., Alcantara L. C. J. Epidemiology of Chikungunya Virus in Bahia, Brazil, 2014–2015. PLoS Currents Outbreaks. 2016;1. doi: 10.1371/currents.outbreaks.c97507e3e48efb946401755d468c28b2 27330849

59. Tatem AJ, Hay SI, Rogers DJ. Global traffic and disease vector dispersal. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(16):6242–7. Epub 2006/04/12. doi: 10.1073/pnas.0508391103 16606847; PubMed Central PMCID: PMC1435368.

60. Yebra G, Ragonnet-Cronin M, Ssemwanga D, Parry CM, Logue CH, Cane PA, et al. Analysis of the History and Spread of HIV-1 in Uganda using Phylodynamics. The Journal of general virology. 2015. Epub 2015/03/01. doi: 10.1099/vir.0.000107 25724670.

61. Schneider WH. Smallpox in Africa during colonial rule. Med Hist. 2009;53(2):193–227. doi: 10.1017/s002572730000363x 19367346; PubMed Central PMCID: PMC2668906.

62. Faria NR, Suchard MA, Rambaut A, Streicker DG, Lemey P. Simultaneously reconstructing viral cross-species transmission history and identifying the underlying constraints. Philos Trans R Soc Lond B Biol Sci. 2013;368(1614):20120196. Epub 2013/02/06. doi: 10.1098/rstb.2012.0196 23382420; PubMed Central PMCID: PMC3678322.

63. Lemey P, Rambaut A, Bedford T, Faria N, Bielejec F, Baele G, et al. Unifying viral genetics and human transportation data to predict the global transmission dynamics of human influenza H3N2. PLoS pathogens. 2014;10(2):e1003932. Epub 2014/03/04. doi: 10.1371/journal.ppat.1003932 24586153; PubMed Central PMCID: PMC3930559.

64. Nunes MR, Palacios G, Faria NR, Sousa EC Jr., Pantoja JA, Rodrigues SG, et al. Air travel is associated with intracontinental spread of dengue virus serotypes 1–3 in Brazil. PLoS Negl Trop Dis. 2014;8(4):e2769. Epub 2014/04/20. doi: 10.1371/journal.pntd.0002769 24743730; PubMed Central PMCID: PMC3990485.

65. Abecasis AB, Vandamme AM, Lemey P. Quantifying differences in the tempo of human immunodeficiency virus type 1 subtype evolution. Journal of virology. 2009;83(24):12917–24. doi: 10.1128/JVI.01022-09 19793809; PubMed Central PMCID: PMC2786833.

66. Raghwani J, Redd AD, Longosz AF, Wu CH, Serwadda D, Martens C, et al. Evolution of HIV-1 within untreated individuals and at the population scale in Uganda. PLoS pathogens. 2018;14(7):e1007167. Epub 2018/07/28. doi: 10.1371/journal.ppat.1007167 30052678; PubMed Central PMCID: PMC6082572.

67. Li G, Piampongsant S, Faria NR, Voet A, Pineda-Pena AC, Khouri R, et al. An integrated map of HIV genome-wide variation from a population perspective. Retrovirology. 2015;12:18. doi: 10.1186/s12977-015-0148-6 25808207; PubMed Central PMCID: PMC4358901.

68. Dennis AM, Herbeck JT, Brown AL, Kellam P, de Oliveira T, Pillay D, et al. Phylogenetic studies of transmission dynamics in generalized HIV epidemics: an essential tool where the burden is greatest? Journal of acquired immune deficiency syndromes. 2014;67(2):181–95. Epub 2014/07/01. doi: 10.1097/QAI.0000000000000271 24977473; PubMed Central PMCID: PMC4304655.

69. Ferguson AG, Morris CN. Mapping transactional sex on the Northern Corridor highway in Kenya. Health & place. 2007;13(2):504–19. Epub 2006/07/04. doi: 10.1016/j.healthplace.2006.05.009 16815730.

70. Muwonga J, Edidi S, Butel C, Vidal N, Monleau M, Okenge A, et al. Resistance to antiretroviral drugs in treated and drug-naive patients in the Democratic Republic of Congo. Journal of acquired immune deficiency syndromes. 2011;57 Suppl 1:S27–33. Epub 2011/10/01. doi: 10.1097/QAI.0b013e31821f596c 21857282.

71. Pineda-Pena AC, Faria NR, Imbrechts S, Libin P, Abecasis AB, Deforche K, et al. Automated subtyping of HIV-1 genetic sequences for clinical and surveillance purposes: performance evaluation of the new REGA version 3 and seven other tools. Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases. 2013;19:337–48. Epub 2013/05/11. doi: 10.1016/j.meegid.2013.04.032 23660484.

72. Struck D, Lawyer G, Ternes AM, Schmit JC, Bercoff DP. COMET: adaptive context-based modeling for ultrafast HIV-1 subtype identification. Nucleic acids research. 2014;42(18):e144. Epub 2014/08/15. doi: 10.1093/nar/gku739 25120265.

73. Djoko CF, Rimoin AW, Vidal N, Tamoufe U, Wolfe ND, Butel C, et al. High HIV type 1 group M pol diversity and low rate of antiretroviral resistance mutations among the uniformed services in Kinshasa, Democratic Republic of the Congo. AIDS research and human retroviruses. 2011;27(3):323–9. doi: 10.1089/aid.2010.0201 20954909; PubMed Central PMCID: PMC3048816.

74. Koch N, Ndihokubwayo JB, Yahi N, Tourres C, Fantini J, Tamalet C. Genetic analysis of hiv type 1 strains in bujumbura (burundi): predominance of subtype c variant. AIDS research and human retroviruses. 2001;17(3):269–73. Epub 2001/02/15. doi: 10.1089/088922201750063205 11177411.

75. Vidal N, Niyongabo T, Nduwimana J, Butel C, Ndayiragije A, Wakana J, et al. HIV type 1 diversity and antiretroviral drug resistance mutations in Burundi. AIDS research and human retroviruses. 2007;23(1):175–80. Epub 2007/02/01. doi: 10.1089/aid.2006.0126 17263648.

76. Hue S, Hassan AS, Nabwera H, Sanders EJ, Pillay D, Berkley JA, et al. HIV type 1 in a rural coastal town in Kenya shows multiple introductions with many subtypes and much recombination. AIDS research and human retroviruses. 2012;28(2):220–4. doi: 10.1089/aid.2011.0048 21770741; PubMed Central PMCID: PMC3275924.

77. Lihana RW, Khamadi SA, Lwembe RM, Kinyua JG, Muriuki JK, Lagat NJ, et al. HIV-1 subtype and viral tropism determination for evaluating antiretroviral therapy options: an analysis of archived Kenyan blood samples. BMC infectious diseases. 2009;9:215. Epub 2009/12/31. doi: 10.1186/1471-2334-9-215 20040114; PubMed Central PMCID: PMC2804586.

78. Sigaloff KC, Mandaliya K, Hamers RL, Otieno F, Jao IM, Lyagoba F, et al. Short communication: High prevalence of transmitted antiretroviral drug resistance among newly HIV type 1 diagnosed adults in Mombasa, Kenya. AIDS research and human retroviruses. 2012;28(9):1033–7. doi: 10.1089/AID.2011.0348 22149307.

79. Galluzzo CM, Germinario EA, Bassani L, Mancini MG, Okong P, Vyankandondera J, et al. Antiretroviral resistance mutations in untreated pregnant women with HIV infection in Uganda and Rwanda. AIDS research and human retroviruses. 2007;23(11):1449–51. Epub 2008/01/11. doi: 10.1089/aid.2007.0109 18184089.

80. Mosha F, Urassa W, Aboud S, Lyamuya E, Sandstrom E, Bredell H, et al. Prevalence of genotypic resistance to antiretroviral drugs in treatment-naive youths infected with diverse HIV type 1 subtypes and recombinant forms in Dar es Salaam, Tanzania. AIDS research and human retroviruses. 2011;27(4):377–82. Epub 2010/10/20. doi: 10.1089/aid.2010.0113 20954839.

81. Somi GR, Kibuka T., Diallo K., Tuhuma T., Bennett D.E., Yang C., Kagoma C., Lyamuya E.F., Swai R.O., Kassim S. Surveillance of transmitted HIV drug resistance among women attending antenatal clinics in Dar es Salaam, Tanzania. Antiviral therapy. 2008;13 (Suppl 2):77–82.

82. Yang C, McNulty A, Diallo K, Zhang J, Titanji B, Kassim S, et al. Development and application of a broadly sensitive dried-blood-spot-based genotyping assay for global surveillance of HIV-1 drug resistance. Journal of clinical microbiology. 2010;48(9):3158–64. Epub 2010/07/28. doi: 10.1128/JCM.00564-10 20660209; PubMed Central PMCID: PMC2937690.

83. Eshleman SH, Laeyendecker O, Parkin N, Huang W, Chappey C, Paquet AC, et al. Antiretroviral drug susceptibility among drug-naive adults with recent HIV infection in Rakai, Uganda. AIDS. 2009;23(7):845–52. Epub 2009/03/12. doi: 10.1097/QAD.0b013e328327957a 19276794; PubMed Central PMCID: PMC2676205.

84. Gale CV, Yirrell DL, Campbell E, Van der Paal L, Grosskurth H, Kaleebu P. Genotypic variation in the pol gene of HIV type 1 in an antiretroviral treatment-naive population in rural southwestern Uganda. AIDS research and human retroviruses. 2006;22(10):985–92. Epub 2006/10/28. doi: 10.1089/aid.2006.22.985 17067268.

85. Hamers RL, Wallis CL, Kityo C, Siwale M, Mandaliya K, Conradie F, et al. HIV-1 drug resistance in antiretroviral-naive individuals in sub-Saharan Africa after rollout of antiretroviral therapy: a multicentre observational study. The Lancet infectious diseases. 2011;11(10):750–9. Epub 2011/08/02. doi: 10.1016/S1473-3099(11)70149-9 21802367.

86. Nazziwa J, Njai HF, Ndembi N, Birungi J, Lyagoba F, Gershim A, et al. Short communication: HIV type 1 transmitted drug resistance and evidence of transmission clusters among recently infected antiretroviral-naive individuals from Ugandan fishing communities of Lake Victoria. AIDS research and human retroviruses. 2013;29(5):788–95. Epub 2012/11/24. doi: 10.1089/AID.2012.0123 23173702; PubMed Central PMCID: PMC3636596.

87. Ndembi N, Lyagoba F, Nanteza B, Kushemererwa G, Serwanga J, Katongole-Mbidde E, et al. Transmitted antiretroviral drug resistance surveillance among newly HIV type 1-diagnosed women attending an antenatal clinic in Entebbe, Uganda. AIDS research and human retroviruses. 2008;24(6):889–95. Epub 2008/06/12. doi: 10.1089/aid.2007.0317 18544019.

88. Ssemwanga D, Ndembi N, Lyagoba F, Magambo B, Kapaata A, Bukenya J, et al. Transmitted antiretroviral drug resistance among drug-naive female sex workers with recent infection in Kampala, Uganda. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2012;54 Suppl 4:S339–42. Epub 2012/05/11. doi: 10.1093/cid/cir937 22544200.

89. Bennett DE, Camacho RJ, Otelea D, Kuritzkes DR, Fleury H, Kiuchi M, et al. Drug resistance mutations for surveillance of transmitted HIV-1 drug-resistance: 2009 update. PloS one. 2009;4(3):e4724. Epub 2009/03/07. doi: 10.1371/journal.pone.0004724 19266092; PubMed Central PMCID: PMC2648874.

90. Katoh K, Kuma K, Miyata T, Toh H. Improvement in the accuracy of multiple sequence alignment program MAFFT. Genome informatics International Conference on Genome Informatics. 2005;16(1):22–33. 16362903.

91. Price MN, Dehal PS, Arkin AP. FastTree 2—approximately maximum-likelihood trees for large alignments. PloS one. 2010;5(3):e9490. doi: 10.1371/journal.pone.0009490 20224823; PubMed Central PMCID: PMC2835736.

92. Rambaut A. Path-O-Gen v1.4 2014. Available from: http://tree.bio.ed.ac.uk/software/pathogen/.

93. Parker J, Rambaut A, Pybus OG. Correlating viral phenotypes with phylogeny: accounting for phylogenetic uncertainty. Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases. 2008;8(3):239–46. doi: 10.1016/j.meegid.2007.08.001 17921073.

94. Wang TH, Donaldson YK, Brettle RP, Bell JE, Simmonds P. Identification of shared populations of human immunodeficiency virus type 1 infecting microglia and tissue macrophages outside the central nervous system. Journal of virology. 2001;75(23):11686–99. Epub 2001/11/02. doi: 10.1128/JVI.75.23.11686-11699.2001 11689650; PubMed Central PMCID: PMC114755.

95. Pond SL, Frost SD, Muse SV. HyPhy: hypothesis testing using phylogenies. Bioinformatics. 2005;21(5):676–9. Epub 2004/10/29. doi: 10.1093/bioinformatics/bti079 15509596.

96. Bruen TC, Philippe H, Bryant D. A simple and robust statistical test for detecting the presence of recombination. Genetics. 2006;172(4):2665–81. Epub 2006/02/21. doi: 10.1534/genetics.105.048975 16489234; PubMed Central PMCID: PMC1456386.

97. Huson DH. SplitsTree: analyzing and visualizing evolutionary data. Bioinformatics. 1998;14(1):68–73. Epub 1998/04/01. doi: 10.1093/bioinformatics/14.1.68 9520503.

98. Murrell B, Wertheim JO, Moola S, Weighill T, Scheffler K, Kosakovsky Pond SL. Detecting individual sites subject to episodic diversifying selection. PLoS genetics. 2012;8(7):e1002764. Epub 2012/07/19. doi: 10.1371/journal.pgen.1002764 22807683; PubMed Central PMCID: PMC3395634.

99. Smith MD, Wertheim JO, Weaver S, Murrell B, Scheffler K, Kosakovsky Pond SL. Less is more: an adaptive branch-site random effects model for efficient detection of episodic diversifying selection. Molecular biology and evolution. 2015;32(5):1342–53. Epub 2015/02/24. doi: 10.1093/molbev/msv022 25697341; PubMed Central PMCID: PMC4408413.

100. Drummond AJ, Suchard MA, Xie D, Rambaut A. Bayesian phylogenetics with BEAUti and the BEAST 1.7. Molecular biology and evolution. 2012;29(8):1969–73. doi: 10.1093/molbev/mss075 22367748; PubMed Central PMCID: PMC3408070.

101. Suchard MA, Rambaut A. Many-core algorithms for statistical phylogenetics. Bioinformatics. 2009;25(11):1370–6. doi: 10.1093/bioinformatics/btp244 19369496; PubMed Central PMCID: PMC2682525.

102. Yang Z. Maximum likelihood phylogenetic estimation from DNA sequences with variable rates over sites: approximate methods. Journal of molecular evolution. 1994;39(3):306–14. Epub 1994/09/01. doi: 10.1007/bf00160154 7932792.

103. Drummond AJ, Ho SY, Phillips MJ, Rambaut A. Relaxed phylogenetics and dating with confidence. PLoS biology. 2006;4(5):e88. Epub 2006/05/11. doi: 10.1371/journal.pbio.0040088 16683862; PubMed Central PMCID: PMC1395354.

104. Baele G, Lemey P, Bedford T, Rambaut A, Suchard MA, Alekseyenko AV. Improving the accuracy of demographic and molecular clock model comparison while accommodating phylogenetic uncertainty. Molecular biology and evolution. 2012;29(9):2157–67. doi: 10.1093/molbev/mss084 22403239; PubMed Central PMCID: PMC3424409.

105. Baele G, Li WL, Drummond AJ, Suchard MA, Lemey P. Accurate model selection of relaxed molecular clocks in bayesian phylogenetics. Molecular biology and evolution. 2013;30(2):239–43. doi: 10.1093/molbev/mss243 23090976; PubMed Central PMCID: PMC3548314.

106. Gill MS, Lemey P, Faria NR, Rambaut A, Shapiro B, Suchard MA. Improving Bayesian population dynamics inference: a coalescent-based model for multiple loci. Molecular biology and evolution. 2013;30(3):713–24. doi: 10.1093/molbev/mss265 23180580; PubMed Central PMCID: PMC3563973.

107. Ferreira MAR, Suchard MA. Bayesian analysis of elapsed times in continuous-time Markov chains. Can J Stat. 2008;36(3):355–68. WOS:000260087000002.

108. Gu Z, Gu L, Eils R, Schlesner M, Brors B. circlize Implements and enhances circular visualization in R. Bioinformatics. 2014;30(19):2811–2. doi: 10.1093/bioinformatics/btu393 24930139.

109. Ferreira MAR, Suchard M. A. Bayesian analysis of elapsed times in continuous-time Markov chains. Canadian Journal of Statistics. 2008;36(3):355–68.

110. Bielejec F, Rambaut A, Suchard MA, Lemey P. SPREAD: Spatial phylogenetic reconstruction of evolutionary dynamics. Bioinformatics. 2011;27: 2910–2912. doi: 10.1093/bioinformatics/btr481 21911333

111. Dellicour S, Rose R, Faria NR, Lemey P, Pybus OG. SERAPHIM: studying environmental rasters and phylogenetically-informed movements. Bioinformatics. 2016. doi: 10.1093/bioinformatics/btw384 27334476.

112. Bouckaert R, Heled J, Kuhnert D, Vaughan T, Wu CH, Xie D, et al. BEAST 2: a software platform for Bayesian evolutionary analysis. PLoS computational biology. 2014;10(4):e1003537. Epub 2014/04/12. doi: 10.1371/journal.pcbi.1003537 24722319; PubMed Central PMCID: PMC3985171.

113. UNAIDS. Global Reports—UNAIDS report on the global AIDS epidemic 2013. 2013.