A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy

Roger Paredes; Maria Carmen Puertas; Wendy Bannister; Mónica Kisic; Alessandro Cozzi-Lepri; Christian Pou; Rocío Bellido; Gilberto Betancor; Johannes Bogner; Panagiotis Gargalianos; Dénes Bánhegyi; Bonaventura Clotet; Jens Lundgren; Luis Menéndez-Arias; Javier Martinez-Picado; The EuroSIDA Study Group

doi:10.1093/infdis/jir385

A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy

Roger Paredes, Maria Carmen Puertas, Wendy Bannister, Mónica Kisic, Alessandro Cozzi-Lepri, Christian Pou, Rocío Bellido, Gilberto Betancor, Johannes Bogner, Panagiotis Gargalianos, Dénes Bánhegyi, Bonaventura Clotet, Jens Lundgren, Luis Menéndez-Arias, Javier Martinez-Picado, The EuroSIDA Study Group

Department of Immunology and Microbiology

14 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Journal of Infectious Diseases
Volume	204
Issue number	5
Pages (from-to)	741-52
Number of pages	12
ISSN	0022-1899
DOIs	https://doi.org/10.1093/infdis/jir385 https://doi.org/10.1093/infdis/jir385
Publication status	Published - 1 Sept 2011

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Paredes, R., Puertas, M. C., Bannister, W., Kisic, M., Cozzi-Lepri, A., Pou, C., Bellido, R., Betancor, G., Bogner, J., Gargalianos, P., Bánhegyi, D., Clotet, B., Lundgren, J., Menéndez-Arias, L., Martinez-Picado, J., & The EuroSIDA Study Group (2011). A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy. Journal of Infectious Diseases, 204(5), 741-52. https://doi.org/10.1093/infdis/jir385, https://doi.org/10.1093/infdis/jir385

Paredes, R, Puertas, MC, Bannister, W, Kisic, M, Cozzi-Lepri, A, Pou, C, Bellido, R, Betancor, G, Bogner, J, Gargalianos, P, Bánhegyi, D, Clotet, B, Lundgren, J, Menéndez-Arias, L, Martinez-Picado, J & The EuroSIDA Study Group 2011, 'A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy', Journal of Infectious Diseases, vol. 204, no. 5, pp. 741-52. https://doi.org/10.1093/infdis/jir385, https://doi.org/10.1093/infdis/jir385

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title = "A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy",

abstract = "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.",

author = "Roger Paredes and Puertas, {Maria Carmen} and Wendy Bannister and M{\'o}nica Kisic and Alessandro Cozzi-Lepri and Christian Pou and Roc{\'i}o Bellido and Gilberto Betancor and Johannes Bogner and Panagiotis Gargalianos and D{\'e}nes B{\'a}nhegyi and Bonaventura Clotet and Jens Lundgren and Luis Men{\'e}ndez-Arias and Javier Martinez-Picado and {The EuroSIDA Study Group}",

year = "2011",

month = sep,

day = "1",

doi = "10.1093/infdis/jir385",

language = "English",

volume = "204",

pages = "741--52",

journal = "Journal of Infectious Diseases",

issn = "0022-1899",

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TY - JOUR

T1 - A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy

AU - Paredes, Roger

AU - Puertas, Maria Carmen

AU - Bannister, Wendy

AU - Kisic, Mónica

AU - Cozzi-Lepri, Alessandro

AU - Pou, Christian

AU - Bellido, Rocío

AU - Betancor, Gilberto

AU - Bogner, Johannes

AU - Gargalianos, Panagiotis

AU - Bánhegyi, Dénes

AU - Clotet, Bonaventura

AU - Lundgren, Jens

AU - Menéndez-Arias, Luis

AU - Martinez-Picado, Javier

AU - The EuroSIDA Study Group

PY - 2011/9/1

Y1 - 2011/9/1

N2 - 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.

AB - 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.

U2 - 10.1093/infdis/jir385

DO - 10.1093/infdis/jir385

M3 - Journal article

C2 - 21844300

SN - 0022-1899

VL - 204

SP - 741

EP - 752

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

IS - 5

ER -

A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy

Abstract

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