TY - JOUR
T1 - Comparative replication capacity of raltegravir-resistant strains and antiviral activity of the new-generation integrase inhibitor dolutegravir in human primary macrophages and lymphocytes
AU - Pollicita, Michela
AU - Surdo, Matteo
AU - di Santo, Fabiola
AU - Cortese, Maria Francesca
AU - Fabeni, Lavinia
AU - Fedele, Valentina
AU - Malet, Isabelle
AU - Marcelin, Anne Genevieve
AU - Calvez, Vincent
AU - Ceccherini-Silberstein, Francesca
AU - Perno, Carlo Federico
AU - Svicher, Valentina
PY - 2014
Y1 - 2014
N2 - Objectives: To evaluate the replication capacity and phenotypic susceptibility to dolutegravir and raltegravir of wild-type and raltegravir-resistant HIV-1 strains in several cellular systems. Methods: The antiviral activities of dolutegravir and raltegravir were evaluated in human primary monocytederived macrophages (MDMs), peripheral blood mononuclear cells (PBMCs) and C8166 T lymphocytic cells. The following raltegravir resistance mutations were analysed: N155H, Y143C, N155H+Y143C and G140S+Q148H. Results: In the absence of drug, the replication capacity of raltegravir-resistant viruses was strongly reduced compared with wild-type in all cellular models analysed. In MDMs and PBMCs, a dramatic decrease in viral replication was observed for the double mutants N155H+Y143C and G140S+Q148H (ranging from 0.1% to 2.5% compared with wild-type). In MDMs, dolutegravir exhibited high potency, with EC50 and EC90 values of 1.1±0.9 and 5.5±3.4 nM, respectively (comparable to raltegravir). These values (particularly for EC90) were significantly lower than those observed in PBMCs (EC50: 2.7±1.5 nM; EC90: 14.8+0.9 nM) and C8166 cells (EC50: 5.5±0.8 nM; EC90: 64.8±5.8 nM). In all cellular models analysed, dolutegravir showed full efficacy against N155H and Y143C mutants (dolutegravir fold-change resistance ranging from 0.1 to 1.4; raltegravir fold-change resistance ranging from 0.1 to 10.3). In C8166 (the only cell model in which replication capacity was sufficient to perform the test) dolutegravir showed full efficacy against mutations N155H+Y143C (dolutegravir fold-change resistance: 0.6) and a slightly lower activity against G140S+Q148H (dolutegravir fold-change resistance: 2.1). Conclusions: Dolutegravir is effective in different HIV cellular targets and against raltegravir-resistant mutants. The high efficacy of dolutegravir in MDMs (cells with limited metabolism) has relevant clinical implications in light of the role of MDMs in the transmission of HIV infection and dissemination in different body compartments.
AB - Objectives: To evaluate the replication capacity and phenotypic susceptibility to dolutegravir and raltegravir of wild-type and raltegravir-resistant HIV-1 strains in several cellular systems. Methods: The antiviral activities of dolutegravir and raltegravir were evaluated in human primary monocytederived macrophages (MDMs), peripheral blood mononuclear cells (PBMCs) and C8166 T lymphocytic cells. The following raltegravir resistance mutations were analysed: N155H, Y143C, N155H+Y143C and G140S+Q148H. Results: In the absence of drug, the replication capacity of raltegravir-resistant viruses was strongly reduced compared with wild-type in all cellular models analysed. In MDMs and PBMCs, a dramatic decrease in viral replication was observed for the double mutants N155H+Y143C and G140S+Q148H (ranging from 0.1% to 2.5% compared with wild-type). In MDMs, dolutegravir exhibited high potency, with EC50 and EC90 values of 1.1±0.9 and 5.5±3.4 nM, respectively (comparable to raltegravir). These values (particularly for EC90) were significantly lower than those observed in PBMCs (EC50: 2.7±1.5 nM; EC90: 14.8+0.9 nM) and C8166 cells (EC50: 5.5±0.8 nM; EC90: 64.8±5.8 nM). In all cellular models analysed, dolutegravir showed full efficacy against N155H and Y143C mutants (dolutegravir fold-change resistance ranging from 0.1 to 1.4; raltegravir fold-change resistance ranging from 0.1 to 10.3). In C8166 (the only cell model in which replication capacity was sufficient to perform the test) dolutegravir showed full efficacy against mutations N155H+Y143C (dolutegravir fold-change resistance: 0.6) and a slightly lower activity against G140S+Q148H (dolutegravir fold-change resistance: 2.1). Conclusions: Dolutegravir is effective in different HIV cellular targets and against raltegravir-resistant mutants. The high efficacy of dolutegravir in MDMs (cells with limited metabolism) has relevant clinical implications in light of the role of MDMs in the transmission of HIV infection and dissemination in different body compartments.
KW - HIV infection
KW - Inhibition of viral replication
KW - Primary cells
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U2 - 10.1093/jac/dku144
DO - 10.1093/jac/dku144
M3 - Article
C2 - 24860155
AN - SCOPUS:84905984152
VL - 69
SP - 2412
EP - 2419
JO - Journal of Antimicrobial Chemotherapy
JF - Journal of Antimicrobial Chemotherapy
SN - 0305-7453
IS - 9
M1 - dku144
ER -