A376s in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy
| Title: | A376s in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy |
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| Authors: | Paredes R.; Puertas M. C.; Bannister W.; Kisic M.; Cozzi-Lepri A.; Pou C.; Bellido R.; Betancor G.; Bogner J.; Gargalianos P.; Banhegyi D.; Clotet B.; Lundgren J.; Menendez-Arias L.; Martinez-Picado J.; Losso M.; Elias C.; Vetter N.; Zangerle R.; Karpov I.; Vassilenko A.; Mitsura V. M.; Suetnov O.; Clumeck N.; De Wit S.; Poll B.; Colebunders R.; Vandekerckhove L.; Hadziosmanovic V.; Kostov K.; Begovac J.; Machala L.; Rozsypal H.; Sedlacek D.; Nielsen J.; Kronborg G.; Benfield T.; Larsen M.; Gerstoft J.; Katzenstein T.; Hansen A. -B. E.; Skinhoj P.; Pedersen C.; Oestergaard L.; Zilmer K.; Smidt J.; Ristola M.; Katlama C.; Viard J. -P.; Girard P. -M.; Livrozet J. M.; Vanhems P.; Pradier C.; Dabis F.; Neau D.; Rockstroh J.; Schmidt R.; Van Lunzen J.; Degen O.; Stellbrink H. J.; Staszewski S.; Fatkenheuer G.; Kosmidis J.; Xylomenos G.; Perdios J.; Panos G.; Filandras A.; Karabatsaki E.; Sambatakou H.; Mulcahy F.; Yust I.; Turner D.; Burke M.; Pollack S.; Hassoun G.; Maayan S.; Vella S.; Esposito R.; Mazeu I.; Mussini C.; Arici C.; Pristera R.; Mazzotta F.; Gabbuti A.; Vullo V.; Lichtner M.; Chirianni A.; Montesarchio E.; Gargiulo M.; Antonucci G.; Iacomi F.; Narciso P.; Vlassi C.; Zaccarelli M.; Lazzarin A.; Finazzi R.; Galli M.; Ridolfo A.; D'Arminio Monforte A.; Rozentale B.; Aldins P.; Chaplinskas S.; Hemmer R.; Staub T.; Reiss P.; Ormaasen V.; Maeland A.; Brunn J.; Knysz B.; Gasiorowski J.; Horban A.; Bakowska E.; Prokopowicz D.; Flisiak R.; Boron-Kaczmarska A.; Pynka M.; Beniowski M.; Mularska E.; Trocha H.; Jablonowska E.; Malolepsza E.; Wojcik K.; Antunes F.; Valadas E.; Mansinho K.; Maltez F.; Duiculescu D.; Rakhmanova A.; Vinogradova E.; Buzunova S.; Jevtovic D.; Mokras M.; Stanekova D.; Tomazic J.; Gonzalez-Lahoz J.; Soriano V.; Martin-Carbonero L.; Labarga P.; Moreno S.; Jou A.; Tural C.; Puig J.; Bravo I.; Gatell J. M.; Miro J. M.; Domingo P.; Gutierrez M.; Mateo G.; Sambeat Ma.; Karlsson A.; Persson P. O.; Flamholc L.; Ledergerber B.; Weber R.; Francioli P.; Cavassini M.; Hirschel B.; Boffi E.; Furrer H.; Battegay M.; Elzi L.; Kravchenko E.; Chentsova N.; Kutsyna G.; Servitskiy S.; Krasnov M.; Barton S.; Johnson A. M.; Mercey D.; Phillips A.; Johnson M. A.; Mocroft A.; Murphy M.; Weber J.; Scullard G.; Fisher M.; Leen C.; Gatell J.; Gazzard B.; Kirk O.; Grint D.; Ellefson M.; Podlekareva D.; Kjaer J.; Peters L.; Reekie J.; Kowalska J.; Tverland J.; Fischer A. H. |
| Contributors: | R. Parede; M.C. Puerta; W. Bannister; M. Kisic; A. Cozzi-Lepri; C. Pou; R. Bellido; G. Betancor; J. Bogner; P. Gargaliano; D. Banhegyi; B. Clotet; J. Lundgren; L. Menendez-Aria; J. Martinez-Picado; M. Losso; C. Elia; N. Vetter; R. Zangerle; I. Karpov; A. Vassilenko; V.M. Mitsura; O. Suetnov; N. Clumeck; S. De Wit; B. Poll; R. Colebunder; L. Vandekerckhove; V. Hadziosmanovic; K. Kostov; J. Begovac; L. Machala; H. Rozsypal; D. Sedlacek; J. Nielsen; G. Kronborg; T. Benfield; M. Larsen; J. Gerstoft; T. Katzenstein; A.-.E. Hansen; P. Skinhoj; C. Pedersen; L. Oestergaard; K. Zilmer; J. Smidt; M. Ristola; C. Katlama; J.-. Viard; P.-. Girard; J.M. Livrozet; P. Vanhem; C. Pradier; F. Dabi; D. Neau; J. Rockstroh; R. Schmidt; J. Van Lunzen; O. Degen; H.J. Stellbrink; S. Staszewski; G. Fatkenheuer; J. Kosmidi; G. Xylomeno; J. Perdio; G. Pano; A. Filandra; E. Karabatsaki; H. Sambatakou; F. Mulcahy; I. Yust; D. Turner; M. Burke; S. Pollack; G. Hassoun; S. Maayan; S. Vella; R. Esposito; I. Mazeu; C. Mussini; C. Arici; R. Pristera; F. Mazzotta; A. Gabbuti; V. Vullo; M. Lichtner; A. Chirianni; E. Montesarchio; M. Gargiulo; G. Antonucci; F. Iacomi; P. Narciso; C. Vlassi; M. Zaccarelli; A. Lazzarin; R. Finazzi; M. Galli |
| Publisher Information: | University of Chicago Press |
| Publication Year: | 2011 |
| Collection: | The University of Milan: Archivio Istituzionale della Ricerca (AIR) |
| Subject Terms: | Adult; Benzoxazine; Drug Resistance; Viral; Female; Genotype; HIV Infection; HIV Reverse Transcriptase; HIV-1; Human; Male; Middle Aged; Models; Molecular; Mutation; Nevirapine; Protein Structure; Tertiary; Reverse Transcriptase Inhibitor; Risk Factor; Treatment Failure; Viral Load; Settore MED/17 - Malattie Infettive |
| Description: | Background. The clinical relevance of mutations in the connection subdomain and the ribonuclease (RNase) H domain of HIV-1 reverse transcriptase (RT) is uncertain. Methods. The risk of virological failure to nonnucleoside RT inhibitor (NNRTI)-based antiretroviral therapy (ART) was evaluated in NNRTI-naive patients who started NNRTIs in the EuroSIDA study after July 1997 according to preexisting substitutions in the connection subdomain and the RNase H domain of HIV-1 RT. An observed association between A376S and virological failure was further investigated by testing in vitro NNRTI susceptibility of single site-directed mutants and patient-derived recombinant viruses. Enzymatic assays also determined the effects of A376S on nevirapine and template-primer binding to HIV-1 RT. Results. Virological failure occurred in 142 of 287 (49%) individuals: 77 receiving nevirapine (67%) and 65 receiving efavirenz (38%) (P < .001). Preexisting A376S was associated with an increased risk of virological failure to nevirapine (relative hazard [RH] = 10.4; 95% confidence interval [CI], 2.0-54.7), but it did not affect efavirenz outcome the same way (RH = 0.5; 95% CI, 0.1-2.2) (P value for interaction 5 .013). A376S conferred selective low-level nevirapine resistance in vitro, and led to greater affinity for double-stranded DNA. Conclusions. The A376S substitution in the connection subdomain of HIV-1 RT causes selective nevirapine resistance and confers an increased risk of virological failure to nevirapine-based ART. |
| Document Type: | article in journal/newspaper |
| Language: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/21844300; info:eu-repo/semantics/altIdentifier/wos/WOS:000294070700011; volume:204; issue:5; firstpage:741; lastpage:752; numberofpages:12; journal:THE JOURNAL OF INFECTIOUS DISEASES; https://hdl.handle.net/2434/774405 |
| DOI: | 10.1093/infdis/jir385 |
| Availability: | https://hdl.handle.net/2434/774405; https://doi.org/10.1093/infdis/jir385 |
| Rights: | info:eu-repo/semantics/openAccess |
| Accession Number: | edsbas.429682D0 |
| Database: | BASE |