title: Gag-Protease Sequence Evolution Following Protease Inhibitor Monotherapy Treatment Failure in HIV-1 Viruses Circulating in East Africa.
abstract: Around 2.5 million HIV-infected individuals failing first-line therapy qualify for boosted protease inhibitor (bPI)-based second-line therapy globally. Major resistance mutations are rarely present at treatment failure in patients receiving bPI and the determinants of failure in these patients remain unknown. There is evidence that Gag can impact PI susceptibility. Here, we have sequenced Gag-Protease before and following failure in 23 patients in the SARA trial infected with subtypes A, C, and D viruses. Before bPI, significant variation in Protease and Gag was observed at positions previously associated with PI exposure and resistance including Gag mutations L449P, S451N, and L453P and Protease K20I and L63P. Following PI failure, previously described mutations in Protease and Gag were observed, including those at the cleavage sites such as R361K and P453L. However, the emergence of clear genetic determinants of therapy failure across patients was not observed. Larger Gag sequence datasets will be required to comprehensively identify mutational correlates of bPI failure across subtypes.
authors.affiliation: 1 University College London , London, United Kingdom .
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Sutherland
authors.affiliation: 2 MRC Clinical Trials Unit at University College London , London, United Kingdom .
authors.forename: Ruth L
authors.initials: RL
authors.lastname: Goodall
authors.affiliation: 1 University College London , London, United Kingdom .
authors.forename: Adele
authors.initials: A
authors.lastname: McCormick
authors.affiliation: 3 Uganda Research Unit on AIDS, Medical Research Council (MRC), Uganda Virus Research Institute , Entebbe, Uganda .
authors.forename: Anne
authors.initials: A
authors.lastname: Kapaata
authors.affiliation: 3 Uganda Research Unit on AIDS, Medical Research Council (MRC), Uganda Virus Research Institute , Entebbe, Uganda .
authors.forename: Fred
authors.initials: F
authors.lastname: Lyagoba
authors.affiliation: 3 Uganda Research Unit on AIDS, Medical Research Council (MRC), Uganda Virus Research Institute , Entebbe, Uganda .
authors.forename: Pontiano
authors.initials: P
authors.lastname: Kaleebu
authors.affiliation: 1 University College London , London, United Kingdom .
authors.forename: Geant
authors.initials: G
authors.lastname: Thiltgen
authors.affiliation: 4 School of Population Health, University of Queensland , Brisbane, Australia .
authors.forename: Charles F
authors.initials: CF
authors.lastname: Gilks
authors.affiliation: 2 MRC Clinical Trials Unit at University College London , London, United Kingdom .
authors.forename: Moira
authors.initials: M
authors.lastname: Spyer
authors.affiliation: 5 Joint Clinical Research Centre , Kampala, Uganda .
authors.forename: Cissy
authors.initials: C
authors.lastname: Kityo
authors.affiliation: 1 University College London , London, United Kingdom .|6 Wellcome Trust Africa Centre for Health and Population Sciences, University of KwaZulu Natal , Mtubatuba, South Africa .
authors.forename: Deenan
authors.initials: D
authors.lastname: Pillay
authors.affiliation: 2 MRC Clinical Trials Unit at University College London , London, United Kingdom .
authors.forename: David
authors.initials: D
authors.lastname: Dunn
authors.affiliation: 1 University College London , London, United Kingdom .
authors.forename: Ravindra K
authors.initials: RK
authors.lastname: Gupta
mesh_terms: D000351:Africa, Eastern; D019943:Amino Acid Substitution; D019143:Evolution, Molecular; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA; D017211:Treatment Failure
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1