title: Intrapatient Evolutionary Dynamics of Human Immunodeficiency Virus Type 1 in Individuals Undergoing Alternative Treatment Strategies with Reverse Transcriptase Inhibitors.
abstract: Structured treatment interruption (STI) has been trialed as an alternative to lifelong antiretroviral therapy (ART). We retrospectively performed single genome sequencing of the HIV-1 pol region from three patients representing different scenarios. They were either failing on continuous therapy (CT-F), failing STI (STI-F), or suppressing on STI (STI-S). Over 460 genomes were generated from three to five different time points over a 2-year period. We found multiple-linked-resistant mutations in both treatment failures. However, the CT-F patient showed a stepwise accumulation of diverse, linked mutations whereas the STI-F patient had lineage turnover between treatment periods with recirculation of wild-type and resistant variants from reservoirs. The STI-F patient showed a 7-fold increase in the third codon position substitution rate relative to the first and second positions compared to a 2-fold increase for CT-F and increased purifying selection in the pol gene (62 vs. 22 sites, respectively). An understanding of intrapatient viral dynamics could guide the future direction of treatment interruption strategies.
authors.affiliation: 1 Uganda Virus Research Institute (UVRI) , Uganda Research Unit on AIDS, Entebbe, Uganda .
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Kayondo
authors.affiliation: 2 Medical Research Council (MRC)/UVRI , Uganda Research Unit on AIDS, Entebbe, Uganda .
authors.forename: Nicaise
authors.initials: N
authors.lastname: Ndembi
authors.affiliation: 2 Medical Research Council (MRC)/UVRI , Uganda Research Unit on AIDS, Entebbe, Uganda .
authors.forename: Chris M
authors.initials: CM
authors.lastname: Parry
authors.affiliation: 3 Virus Reference Department, Public Health England , London, United Kingdom .
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Cane
authors.affiliation: 4 Department of Infection and Immunity, University College London , London, United Kingdom .
authors.forename: Stephane
authors.initials: S
authors.lastname: Hué
authors.affiliation: 5 MRC Clinical Trials Unit, University College London , London, United Kingdom .
authors.forename: Ruth
authors.initials: R
authors.lastname: Goodall
authors.affiliation: 5 MRC Clinical Trials Unit, University College London , London, United Kingdom .
authors.forename: David T
authors.initials: DT
authors.lastname: Dunn
authors.affiliation: 1 Uganda Virus Research Institute (UVRI) , Uganda Research Unit on AIDS, Entebbe, Uganda .|2 Medical Research Council (MRC)/UVRI , Uganda Research Unit on AIDS, Entebbe, Uganda .
authors.forename: Pontiano
authors.initials: P
authors.lastname: Kaleebu
authors.affiliation: 4 Department of Infection and Immunity, University College London , London, United Kingdom .
authors.forename: Deenan
authors.initials: D
authors.lastname: Pillay
authors.affiliation: 3 Virus Reference Department, Public Health England , London, United Kingdom .
authors.forename: Jean L
authors.initials: JL
authors.lastname: Mbisa
mesh_terms: D000220:Adaptation, Biological; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D016000:Cluster Analysis; D019143:Evolution, Molecular; D014644:Genetic Variation; D016679:Genome, Viral; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000145:classification* / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D010802:Phylogeny; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D017385:Sequence Homology; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D054302:pol Gene Products, Human Immunodeficiency Virus