HIV drug resistance against strand transfer integrase inhibitors

被引:144
作者
Anstett, Kaitlin [1 ,2 ]
Brenner, Bluma [2 ]
Mesplede, Thibault [2 ]
Wainberg, Mark A. [1 ,2 ]
机构
[1] McGill Univ, Dept Microbiol & Immunol, Fac Med, Montreal, PQ, Canada
[2] Jewish Gen Hosp, Lady Davis Inst Med Res, McGill AIDS Ctr, 3755 Cote Ste Catherine Rd, Montreal, PQ, Canada
基金
加拿大健康研究院;
关键词
HIV; Resistance; Selections; Clinic; INSTIs; Raltegravir; Elvitegravir; Dolutegravir; Cabotegravir; Bictegravir; REVERSE-TRANSCRIPTASE INHIBITORS; ANTIRETROVIRAL-NAIVE ADULTS; LOW-LEVEL RESISTANCE; DOLUTEGRAVIR RESISTANCE; CROSS-RESISTANCE; RALTEGRAVIR RESISTANCE; DOUBLE-BLIND; IN-VITRO; POLYMORPHIC SUBSTITUTION; ANTIVIRAL ACTIVITY;
D O I
10.1186/s12977-017-0360-7
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Integrase strand transfer inhibitors (INSTIs) are the newest class of antiretroviral drugs to be approved for treatment and act by inhibiting the essential HIV protein integrase from inserting the viral DNA genome into the host cell's chromatin. Three drugs of this class are currently approved for use in HIV-positive individuals: raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG), while cabotegravir (CAB) and bictegravir (BIC) are currently in clinical trials. RAL and EVG have been successful in clinical settings but have relatively low genetic barriers to resistance. Furthermore, they share a high degree of cross-resistance, which necessitated the development of so-called second-generation drugs of this class (DTG, CAB, and BIC) that could retain activity against these resistant variants. In vitro selection experiments have been instrumental to the clinical development of INSTIs, however they cannot completely recapitulate the situation in an HIV-positive individual. This review summarizes and compares all the currently available information as it pertains to both in vitro and in vivo selections with all five INSTIs, and the measured fold-changes in resistance of resistant variants in in vitro assays. While the selection of resistance substitutions in response to RAL and EVG bears high similarity in patients as compared to laboratory studies, there is less concurrence regarding the "second-generation" drugs of this class. This highlights the unpredictability of HIV resistance to these inhibitors, which is of concern as CAB and BIC proceed in their clinical development.
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页数:16
相关论文
共 89 条
[1]   Impact of Primary Elvitegravir Resistance-Associated Mutations in HIV-1 Integrase on Drug Susceptibility and Viral Replication Fitness [J].
Abram, Michael E. ;
Hluhanich, Rebecca M. ;
Goodman, Derrick D. ;
Andreatta, Kristen N. ;
Margot, Nicolas A. ;
Ye, Linda ;
Niedziela-Majka, Anita ;
Barnes, Tiffany L. ;
Novikov, Nikolai ;
Chen, Xiaowu ;
Svarovskaia, Evguenia S. ;
McColl, Damian J. ;
White, Kirsten L. ;
Miller, Michael D. .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2013, 57 (06) :2654-2663
[2]  
[Anonymous], 2009, AIDS Alert, V24, P106
[3]   Polymorphic substitution E157Q in HIV-1 integrase increases R263K-mediated dolutegravir resistance and decreases DNA binding activity [J].
Anstett, Kaitlin ;
Cutillas, Vincent ;
Fusco, Robert ;
Mesplede, Thibault ;
Wainberg, Mark A. .
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 2016, 71 (08) :2083-2088
[4]   Dolutegravir-Selected HIV-1 Containing the N155H and R263K Resistance Substitutions Does Not Acquire Additional Compensatory Mutations under Drug Pressure That Lead to Higher-Level Resistance and Increased Replicative Capacity [J].
Anstett, Kaitlin ;
Fusco, Robert ;
Cutillas, Vincent ;
Mesplede, Thibault ;
Wainberg, Mark A. .
JOURNAL OF VIROLOGY, 2015, 89 (20) :10482-10488
[5]   Dolutegravir Resistance Mutation R263K Cannot Coexist in Combination with Many Classical Integrase Inhibitor Resistance Substitutions [J].
Anstett, Kaitlin ;
Mesplede, Thibault ;
Oliveira, Maureen ;
Cutillas, Vincent ;
Wainberg, Mark A. .
JOURNAL OF VIROLOGY, 2015, 89 (08) :4681-4684
[6]   Identification of Novel Mutations Responsible for Resistance to MK-2048, a Second-Generation HIV-1 Integrase Inhibitor [J].
Bar-Magen, Tamara ;
Sloan, Richard D. ;
Donahue, Daniel A. ;
Kuhl, Bjoern D. ;
Zabeida, Alexandra ;
Xu, Hongtao ;
Oliveira, Maureen ;
Hazuda, Daria J. ;
Wainberg, Mark A. .
JOURNAL OF VIROLOGY, 2010, 84 (18) :9210-9216
[7]   Dolutegravir: an exciting new kid on the block [J].
Blanco Arevalo, Jose Luis ;
George Whidock, Gary .
EXPERT OPINION ON PHARMACOTHERAPY, 2014, 15 (04) :573-582
[8]   HIV-1 Integrase Inhibitor Resistance and Its Clinical Implications [J].
Blanco, Jose-Luis ;
Varghese, Vici ;
Rhee, Soo-Yon ;
Gatell, Jose M. ;
Shafer, Robert W. .
JOURNAL OF INFECTIOUS DISEASES, 2011, 203 (09) :1204-1214
[9]   Dynamic Oligomerization of Integrase Orchestrates HIV Nuclear Entry [J].
Borrenberghs, Doortje ;
Dirix, Lieve ;
De Wit, Flore ;
Rocha, Susana ;
Blokken, Jolien ;
De Houwer, Stephanie ;
Gijsbers, Rik ;
Christ, Frauke ;
Hofkens, Johan ;
Hendrix, Jelle ;
Debyser, Zeger .
SCIENTIFIC REPORTS, 2016, 6
[10]   We need to use the best antiretroviral drugs worldwide to prevent HIV drug resistance [J].
Brenner, Bluma ;
Wainberg, Mark A. .
AIDS, 2016, 30 (17) :2725-2727