title: HIV-1 integrase variants retarget viral integration and are associated with disease progression in a chronic infection cohort.
abstract: Distinct integration patterns of different retroviruses, including HIV-1, have puzzled virologists for over 20 years. A tetramer of the viral integrase (IN) assembles on the two viral cDNA ends, docks onto the target DNA (tDNA), and catalyzes viral genome insertion into the host chromatin. We identified the amino acids in HIV-1 IN that directly contact tDNA bases and affect local integration site sequence selection. These residues also determine the propensity of the virus to integrate into flexible tDNA sequences. Remarkably, natural polymorphisms INS119G and INR231G retarget viral integration away from gene-dense regions. Precisely these variants were associated with rapid disease progression in a chronic HIV-1 subtype C infection cohort. These findings link integration site selection to virulence and viral evolution, but also to the host immune response and antiretroviral therapy, since HIV-1 IN119 is under selection by HLA alleles and integrase inhibitors.
authors.affiliation: Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University of Leuven, 3000 Leuven, Belgium; Laboratory for Biomolecular Modeling, Department of Chemistry, KU Leuven-University of Leuven, 3000 Leuven, Belgium.
authors.forename: Jonas
authors.initials: J
authors.lastname: Demeulemeester
authors.affiliation: Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University of Leuven, 3000 Leuven, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Vets
authors.affiliation: Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University of Leuven, 3000 Leuven, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Schrijvers
authors.affiliation: Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University of Leuven, 3000 Leuven, Belgium; HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, 4013 Durban, South Africa.
authors.forename: Paradise
authors.initials: P
authors.lastname: Madlala
authors.affiliation: Laboratory for Biomolecular Modeling, Department of Chemistry, KU Leuven-University of Leuven, 3000 Leuven, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: De Maeyer
authors.affiliation: Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University of Leuven, 3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: De Rijck
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, 4013 Durban, South Africa; KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, 4013 Durban, South Africa; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Max Planck Institute for Infection Biology, Chariteplatz, 10117 Berlin, Germany.
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.affiliation: Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University of Leuven, 3000 Leuven, Belgium. Electronic address: zeger.debyser@med.kuleuven.be.
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.affiliation: Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University of Leuven, 3000 Leuven, Belgium. Electronic address: rik.gijsbers@med.kuleuven.be.
authors.forename: Rik
authors.initials: R
authors.lastname: Gijsbers
mesh_terms: D000595:Amino Acid Sequence; D003001:Cloning, Molecular; D019295:Computational Biology; D004279:DNA, Viral / Q000235:genetics; D018450:Disease Progression; D016679:Genome, Viral; D015658:HIV Infections / Q000201:enzymology*; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D016662:Virus Integration; D014779:Virus Replication
chemical_list: D004279:DNA, Viral; D011994:Recombinant Proteins; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1