title: The Influence of HIV on the Evolution of Mycobacterium tuberculosis.
abstract: HIV significantly affects the immunological environment during tuberculosis coinfection, and therefore may influence the selective landscape upon which M. tuberculosis evolves. To test this hypothesis whole genome sequences were determined for 169 South African M. tuberculosis strains from HIV-1 coinfected and uninfected individuals and analyzed using two Bayesian codon-model based selection analysis approaches: FUBAR which was used to detect persistent positive and negative selection (selection respectively favoring and disfavoring nonsynonymous substitutions); and MEDS which was used to detect episodic directional selection specifically favoring nonsynonymous substitutions within HIV-1 infected individuals. Among the 25,251 polymorphic codon sites analyzed, FUBAR revealed that 189-fold more were detectably evolving under persistent negative selection than were evolving under persistent positive selection. Three specific codon sites within the genes celA2b, katG, and cyp138 were identified by MEDS as displaying significant evidence of evolving under directional selection influenced by HIV-1 coinfection. All three genes encode proteins that may indirectly interact with human proteins that, in turn, interact functionally with HIV proteins. Unexpectedly, epitope encoding regions were enriched for sites displaying weak evidence of directional selection influenced by HIV-1. Although the low degree of genetic diversity observed in our M. tuberculosis data set means that these results should be interpreted carefully, the effects of HIV-1 on epitope evolution in M. tuberculosis may have implications for the design of M. tuberculosis vaccines that are intended for use in populations with high HIV-1 infection rates.
authors.affiliation: Wellcome Centre for Infectious Disease Research in Africa, Institute of Infectious Disease and Molecular Medicine, and Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Anastasia S
authors.initials: AS
authors.lastname: Koch
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Brites
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Stucki
authors.affiliation: Molecular Mycobacteriology Research Unit, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Evans
authors.affiliation: Molecular Mycobacteriology Research Unit, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Ronnett
authors.initials: R
authors.lastname: Seldon
authors.affiliation: Department of Integrative Biomedical Sciences, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Alexa
authors.initials: A
authors.lastname: Heekes
authors.affiliation: Department of Integrative Biomedical Sciences, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Nicola
authors.initials: N
authors.lastname: Mulder
authors.affiliation: University of Cape Town, and National Health Laboratory Service, Cape Town, South Africa.
authors.forename: Mark
authors.initials: M
authors.lastname: Nicol
authors.affiliation: Division of Public Health Medicine, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa.|The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Tolu
authors.initials: T
authors.lastname: Oni
authors.affiliation: Molecular Mycobacteriology Research Unit, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Valerie
authors.initials: V
authors.lastname: Mizrahi
authors.affiliation: Molecular Mycobacteriology Research Unit, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Digby F
authors.initials: DF
authors.lastname: Warner
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Julian
authors.initials: J
authors.lastname: Parkhill
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Gagneux
authors.affiliation: Division of Computational Biology, Department of Integrated Biology Sciences and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Darren P
authors.initials: DP
authors.lastname: Martin
authors.affiliation: Wellcome Centre for Infectious Disease Research in Africa, Institute of Infectious Disease and Molecular Medicine, and Department of Medicine, University of Cape Town, Cape Town, South Africa.|Department of Medicine, Imperial College, London, United Kingdom.|Francis Crick Institute, London, United Kingdom.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wilkinson
mesh_terms: D001499:Bayes Theorem; D003062:Codon; D060085:Coinfection / Q000378:metabolism; D019143:Evolution, Molecular; D014644:Genetic Variation; D015658:HIV Infections / Q000150:complications / Q000235:genetics; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000378:metabolism*; D012641:Selection, Genetic; D014397:Tuberculosis, Pulmonary / Q000150:complications / Q000378:metabolism*
chemical_list: D003062:Codon
keywords: HIV coinfection; Mycobacterium tuberculosis; evolution; natural selection