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AIDS Res Hum Retroviruses. 2017 May 25. doi: 10.1089/AID.2017.0061. [Epub ahead of print]

HIV-1 full-genome phylogenetics of generalized epidemics in sub-Saharan Africa: impact of missing nucleotide characters in next-generation sequences.

Author information

1
Imperial College London School of Public Health, 156430, Department of Infectious Disease Epidemiology, London, United Kingdom of Great Britain and Northern Ireland ; oliver.ratmann@imperial.ac.uk.
2
Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, Oxford, United Kingdom of Great Britain and Northern Ireland ; c.wymant@imperial.ac.uk.
3
Imperial College London, 4615, Department of Mathematics, London, London, United Kingdom of Great Britain and Northern Ireland ; c.colijn@imperial.ac.uk.
4
Africa Centre for Health and Population Studies, University of KwaZulu-Natal, Durban, South Africa ; sdanaviah@africacentre.ac.za.
5
Harvard School of Public Health, Immunology and Infectious Diseases, Boston, Massachusetts, United States.
6
Botswana-Harvard AIDS Institute Partnership, 292006, Gaborone, Gaborone, Botswana ; messex@hsph.harvard.edu.
7
University of Cambridge, Department of Veterinary Medicine, Cambridge, United Kingdom of Great Britain and Northern Ireland ; sdwfrost@gmail.com.
8
University of Cambridge, Department of Veterinary Medicine, Cambridge, United Kingdom of Great Britain and Northern Ireland ; ag711@cam.ac.uk.
9
Botswana-Harvard AIDS Institute Partnership, 292006, Gaborone, Gaborone, Botswana ; sgaseitsiwe@gmail.com.
10
Johns Hopkins University, 1466, Department of Epidemiology, Baltimore, Maryland, United States.
11
Rakai Health Sciences Program, Entebbe, Uganda ; mgrabows@jhu.edu.
12
Rakai Health Sciences Program, Entebbe, Uganda ; rgray4@jhu.edu.
13
University of Auckland, Department of Statistics, Auckland, New Zealand.
14
University of Montpellier, 11 Laboratoire d'Informatique, de Robotique et de Microelectronique de Montpellier , Montpellier, France ; s.guindon@auckland.ac.nz.
15
Medizinische Universitat Wien, 27271, Centre for Integrative Bioinformatics Vienna, Max F. Perutz Laboratories, Wien, Wien, Austria.
16
Wirtschaftsuniversitat Wien, 27254, Bioinformatics and Computational Biology, Wien, Wien, Austria ; arndt.von.haeseler@univie.ac.at.
17
Medical Research Council, Basic Sciences , Plot 51-59 , Nakiwogo Road , P.O.Box 49 , Entebbe, Uganda , +256 ; pontiano.kaleebu@mrcuganda.org.
18
Imperial College London, 4615, Department of Mathematics, London, London, United Kingdom of Great Britain and Northern Ireland ; m.kendall@imperial.ac.uk.
19
Heidelberg Institute for Theoretical Studies, Heidelberg, Germany ; Alexey.Kozlov@h-its.org.
20
Stanford University, Division of Infectious Diseases and Geograhic Medicine , Room S140 , Grant Building , 259 Campus Drive , Stanford, California, United States , 94305.
21
University of KwaZulu-Natal, Africa Centre for Health and Population Studies , Room 135 DDMRI Building , College of Health Sciences , 719 Umbilo Road , Durban, KwaZulu-Natal, South Africa , 4001 ; jmanasa@gmail.com.
22
Medizinische Universitat Wien, 27271, Centre for Integrative Bioinformatics Vienna, Max F. Perutz Laboratories, Wien, Wien, Austria ; minh.bui@univie.ac.at.
23
Botswana-Harvard AIDS Institute Partnership, 292006 , Private Bag BO320 , Gaborone, Botswana.
24
Stellenbosch University Faculty of Medicine and Health Sciences, 121470, Division of Medical Virology, Cape Town, South Africa , 7500 ; sikhulilemoyo@gmail.com.
25
HSPH, Immunology & Infectious Diseases, Boston, Massachusetts, United States.
26
Botswana-Harvard AIDS Institute Partnership, 292006, Gaborone, Gaborone, Botswana ; vnovi@hsph.harvard.edu.
27
MRC/UVRI Uganda Research Unit On AIDS, 47968, Entebbe, Wakiso, Uganda ; ebecca.Nsubuga@mrcuganda.org.
28
Africa Centre for Health & Population Studies, UKZN, Virology Laboratory/ Genomics Unit, Durban, South Africa ; spillay@africacentre.ac.za.
29
Rakai Health Sciences Program, Entebbe, Uganda.
30
National Institute of Allergy and Infectious Diseases, 35037, Division of Intramural Research, Bethesda, Maryland, United States ; tquinn2@jhmi.edu.
31
Rakai Health Sciences Program, Rakai, Uganda.
32
Makerere University, 58588, School of Public Health, Kampala, Kampala, Uganda ; dserwada@imul.com.
33
MRC/UVRI Uganda Research Unit on AIDS, Basic Sciences Program , P.O.Box 49 , Entebbe , Entebbe, Uganda , 49.
34
Uganda ; deogratius.ssemwanga@mrcuganda.org.
35
Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.
36
Karlsruher Institut fur Technologie, 150232, Institute for Theoretical Informatics, Karlsruhe, Baden-Württemberg, Germany ; Alexandros.Stamatakis@h-its.org.
37
Medizinische Universitat Wien, 27271, Centre for Integrative Bioinformatics Vienna, Max F. Perutz Laboratories, Wien, Wien, Austria ; jana.trifinopoulos@gmail.com.
38
Rakai Health Sciences Program, Entebbe, Uganda ; mwawer1@jhu.edu.
39
University of Edinburgh, School of Biological Sciences , Ashworth Building , West Mains Road , Edinburgh, United Kingdom of Great Britain and Northern Ireland , EH9 3JT ; A.Leigh-Brown@ed.ac.uk.
40
University of KwaZulu-Natal College of Health Sciences, 72753, Nelson R. Mandela School of Medicine, Durban, South Africa ; tdeoliveira@africacentre.ac.za.
41
Imperial College London, 4615, Department of Infectious Diseases and Immunity, London, London, United Kingdom of Great Britain and Northern Ireland ; Paul.Kellam@kymab.com.
42
Africa Centre for Health and Population Studies, University of KwaZulu-Natal, Durban, South Africa ; dpillay@africacentre.ac.za.
43
Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, Oxford, United Kingdom of Great Britain and Northern Ireland ; christophe.fraser@gmail.com.

Abstract

To characterize HIV-1 transmission dynamics in regions where the burden of HIV-1 is greatest, the 'Phylogenetics and Networks for Generalised HIV Epidemics in Africa' consortium (PANGEA-HIV) is sequencing full-genome viral isolates from across sub-Saharan Africa. We report the first 3,985 PANGEA-HIV consensus sequences from four cohort sites (Rakai Community Cohort Study, n=2,833; MRC/UVRI Uganda, n=701; Mochudi Prevention Project, n=359; Africa Health Research Institute Resistance Cohort, n=92). Next-generation sequencing success rates varied: more than 80% of the viral genome from the gag to the nef genes could be determined for all sequences from South Africa, 75% of sequences from Mochudi, 60% of sequences from MRC/UVRI Uganda, and 22% of sequences from Rakai. Partial sequencing failure was primarily associated with low viral load, increased for amplicons closer to the 3' end of the genome, was not associated with subtype diversity except HIV-1 subtype D, and remained significantly associated with sampling location after controlling for other factors. We assessed the impact of the missing data patterns in PANGEA-HIV sequences on phylogeny reconstruction in simulations. We found a threshold in terms of taxon sampling below which the patchy distribution of missing characters in next-generation sequences has an excess negative impact on the accuracy of HIV-1 phylogeny reconstruction, which is attributable to tree reconstruction artifacts that accumulate when branches in viral trees are long. The large number of PANGEA-HIV sequences provides unprecedented opportunities for evaluating HIV-1 transmission dynamics across sub-Saharan Africa and identifying prevention opportunities. Molecular epidemiological analyses of these data must proceed cautiously because sequence sampling remains below the identified threshold and a considerable negative impact of missing characters on phylogeny reconstruction is expected.

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