Specific HIV-1 integrase polymorphisms change their prevalence in untreated versus antiretroviral-treated HIV-1-infected patients, all naive to integrase inhibitors

被引:53
作者
Ceccherini-Silberstein, Francesca [1 ]
Malet, Isabelle [2 ]
Fabeni, Lavinia [1 ,3 ]
Dimonte, Salvatore [1 ]
Svicher, Valentina [1 ]
D'Arrigo, Roberta [3 ]
Artese, Anna [4 ]
Costa, Giosue [4 ]
Bono, Sara [1 ]
Alcaro, Stefano [4 ]
Monforte, Antonella d'Arminio [5 ]
Katlama, Christine [6 ]
Calvez, Vincent [2 ]
Antinori, Andrea [3 ]
Marcelin, Anne-Genevieve [2 ]
Perno, Carlo-Federico [1 ,3 ]
机构
[1] Univ Roma Tor Vergata, Dept Expt Med, I-00133 Rome, Italy
[2] Grp Hosp Pitie Salpetriere, AP HP, Dept Virol, F-75013 Paris, France
[3] Natl Inst Infect Dis Lazzaro Spallanzani, I-00149 Rome, Italy
[4] Univ Catanzaro Magna Graecia, Dept Pharmacobiol Sci, I-88100 Catanzaro, Italy
[5] Univ Milan, Inst Infect & Trop Dis, I-20157 Milan, Italy
[6] Grp Hosp Pitie Salpetriere, AP HP, Dept Infect Dis, AIDS Clin Res Unit, F-75013 Paris, France
关键词
HIV drug resistance; integrase; reverse transcriptase; antiretroviral therapy; co-evolution; polymorphisms; molecular docking; IMMUNODEFICIENCY-VIRUS TYPE-1; TREATMENT-EXPERIENCED PATIENTS; REVERSE-TRANSCRIPTASE; RALTEGRAVIR SUSCEPTIBILITY; RESISTANCE MUTATIONS; DNA-BINDING; PHASE-II; RETROVIRAL INTEGRASES; CATALYTIC-ACTIVITY; CROSS-RESISTANCE;
D O I
10.1093/jac/dkq326
中图分类号
R51 [传染病];
学科分类号
100401 ;
摘要
To define whether the prevalence of mutations associated with integrase inhibitor (INI) resistance is different in untreated versus antiretroviral-treated HIV-1-infected individuals (all INI naive). Gene sequences of the integrase (IN) and reverse transcriptase (RT) obtained from plasma samples of a well-defined cohort of 448 HIV-1-infected individuals (134 drug naive and 314 antiretroviral treated) were analysed. Docking simulations, using RT and IN models, were also performed. Primary mutations and the majority of secondary mutations for raltegravir or elvitegravir were completely absent (or rarely found, < 1%) in INI-naive patients, either drug naive or antiretroviral treated. Specific IN polymorphisms increased their frequency in antiretroviral-treated patients, and showed positive associations with specific RT resistance mutations. M154I and V165I IN polymorphisms occurred at a frequency of 6% in untreated patients, reaching 21.3% and 13.4%, respectively, in antiretroviral-treated patients. The mutation M154L, absent in drug-naive patients, was prevalent at 5.7% in antiretroviral-treated patients, and was positively associated with RT resistance mutations F227L and T215Y. Similarly, V165I and G163R mutations were associated with the RT resistance mutations F227L and M230L, respectively, and the T206S polymorphism was associated with the RT resistance mutation L210W. Docking simulations showed several favourable contacts between IN and RT residues. Overall, results confirm that primary and secondary INI-associated mutations are absent or extremely rare in INI-naive patients. Conversely, a few specific IN polymorphisms found in INI-naive patients increased their frequency in antiretroviral-failing patients and/or are associated with RT resistance mutations. The potential contribution of such polymorphisms to the evolution of resistance under the pressure of INIs needs further investigation.
引用
收藏
页码:2305 / 2318
页数:14
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