title: Horizontal gene transfer from human host to HIV-1 reverse transcriptase confers drug resistance and partly compensates for replication deficits.
abstract: We investigated the origin and the effect of insertion D67D-THGERDLGPA within HIV-1 RT from a patient failing antiviral therapy. The insertion developed within the context of pre-existing NRTI and NNRTI mutations (M41L, L210W, T215Y and N348I). Concurrently, the NRTI mutations T69I and V118I and the NNRTI mutations K103N and Y181C were detected for the first time. High-level drug resistance (fold-changes≥50) and a good replication capacity (87% of wild-type) were observed, significantly higher than for the previous virus without insertion. The insertion was very similar to a region within human chromosome 17 (31/34 nucleotide identity), and had already been detected independently in a Japanese HIV-1 isolate. These results suggest that a particular sequence within human chromosome 17 is prone to horizontal gene transfer into the HIV-1 RT finger subdomain. This insertion confers selective advantage to HIV-1 by its contribution to multi-drug resistance and restoration of impaired replication capacity.
authors.affiliation: Rega Institute for Medical Research, Department of Microbiology and Immunology, Minderbroedersstraat 10, KU Leuven, 3000 Leuven, Belgium. Electronic address: sarah.megens@rega.kuleuven.be.
authors.forename: Sarah
authors.initials: S
authors.lastname: Megens
authors.affiliation: AIDS Reference Laboratory, Centre Hospitalier Universitaire de Liège, Liège, Belgium.
authors.forename: Dolores
authors.initials: D
authors.lastname: Vaira
authors.affiliation: Switch Laboratory, VIB, KU Leuven, Leuven, Belgium; Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; Vrije Universiteit Brussel, Brussel, Belgium.
authors.forename: Greet
authors.initials: G
authors.lastname: De Baets
authors.affiliation: Rega Institute for Medical Research, Department of Microbiology and Immunology, Minderbroedersstraat 10, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dekeersmaeker
authors.affiliation: AIDS Reference Laboratory, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Yoeri
authors.initials: Y
authors.lastname: Schrooten
authors.affiliation: Rega Institute for Medical Research, Department of Microbiology and Immunology, Minderbroedersstraat 10, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Guangdi
authors.initials: G
authors.lastname: Li
authors.affiliation: Switch Laboratory, VIB, KU Leuven, Leuven, Belgium; Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Joost
authors.initials: J
authors.lastname: Schymkowitz
authors.affiliation: Switch Laboratory, VIB, KU Leuven, Leuven, Belgium; Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Frederic
authors.initials: F
authors.lastname: Rousseau
authors.affiliation: Rega Institute for Medical Research, Department of Microbiology and Immunology, Minderbroedersstraat 10, KU Leuven, 3000 Leuven, Belgium; Centro de Malária e outras Doenças Tropicais and Unidade de Microbiologia, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Portugal.
authors.forename: Anne-Mieke
authors.initials: AM
authors.lastname: Vandamme
authors.affiliation: AIDS Reference Center, Centre Hospitalier Universitaire de Liège, Liège, Belgium.
authors.forename: Michel
authors.initials: M
authors.lastname: Moutschen
authors.affiliation: Rega Institute for Medical Research, Department of Microbiology and Immunology, Minderbroedersstraat 10, KU Leuven, 3000 Leuven, Belgium; AIDS Reference Laboratory, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Kristel
authors.initials: K
authors.lastname: Van Laethem
mesh_terms: D002877:Chromosomes, Human; D024882:Drug Resistance, Viral; D022761:Gene Transfer, Horizontal; D015658:HIV Infections / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D010802:Phylogeny; D011487:Protein Conformation; D012367:RNA, Viral / Q000235:genetics; D017422:Sequence Analysis, DNA; D017385:Sequence Homology; D014779:Virus Replication
chemical_list: D012367:RNA, Viral; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: Antiretroviral therapy; HIV/AIDS; Insertion; Resistance; Reverse transcriptase