A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy
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 = .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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2011 |
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| Erschienen: |
2011 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:204 |
|---|---|
| Enthalten in: |
The Journal of infectious diseases - 204(2011), 5 vom: 01. Sept., Seite 741-52 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Paredes, Roger [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 19.10.2011 Date Revised 09.12.2020 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/infdis/jir385 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM210777133 |
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| 100 | 1 | |a Paredes, Roger |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy |
| 264 | 1 | |c 2011 | |
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| 500 | |a Date Completed 19.10.2011 | ||
| 500 | |a Date Revised 09.12.2020 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUND: The clinical relevance of mutations in the connection subdomain and the ribonuclease (RNase) H domain of HIV-1 reverse transcriptase (RT) is uncertain | ||
| 520 | |a 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 | ||
| 520 | |a 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 = .013). A376S conferred selective low-level nevirapine resistance in vitro, and led to greater affinity for double-stranded DNA | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Alkynes |2 NLM | |
| 650 | 7 | |a Benzoxazines |2 NLM | |
| 650 | 7 | |a Cyclopropanes |2 NLM | |
| 650 | 7 | |a Reverse Transcriptase Inhibitors |2 NLM | |
| 650 | 7 | |a Nevirapine |2 NLM | |
| 650 | 7 | |a 99DK7FVK1H |2 NLM | |
| 650 | 7 | |a reverse transcriptase, Human immunodeficiency virus 1 |2 NLM | |
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| 650 | 7 | |a HIV Reverse Transcriptase |2 NLM | |
| 650 | 7 | |a EC 2.7.7.49 |2 NLM | |
| 650 | 7 | |a efavirenz |2 NLM | |
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| 700 | 1 | |a Bannister, Wendy |e verfasserin |4 aut | |
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| 700 | 1 | |a Cozzi-Lepri, Alessandro |e verfasserin |4 aut | |
| 700 | 1 | |a Pou, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Bellido, Rocío |e verfasserin |4 aut | |
| 700 | 1 | |a Betancor, Gilberto |e verfasserin |4 aut | |
| 700 | 1 | |a Bogner, Johannes |e verfasserin |4 aut | |
| 700 | 1 | |a Gargalianos, Panagiotis |e verfasserin |4 aut | |
| 700 | 1 | |a Bánhegyi, Dénes |e verfasserin |4 aut | |
| 700 | 1 | |a Clotet, Bonaventura |e verfasserin |4 aut | |
| 700 | 1 | |a Lundgren, Jens |e verfasserin |4 aut | |
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