TY - JOUR
T1 - Quinoline antimalarials as investigational drugs for HIV-1/AIDS
T2 - In vitro effects on HIV-1 replication, HIV-1 response to antiretroviral drugs, and intracellular antiretroviral drug concentrations
AU - Savarino, Andrea
AU - Lucia, Mothanje B.
AU - Heine, Rob Ter
AU - Rastrelli, Elena
AU - Rutella, Sergio
AU - Majori, Giancarlo
AU - Huitema, Alwin
AU - Boelaert, Johan R.
AU - Cauda, Roberto
PY - 2006/10
Y1 - 2006/10
N2 - In this study, the effects of the quinoline antimalarials, chloroquine and mefloquine, were tested on: (1) HIV-1 replication; (2) virus response to existing antiretrovirals; (3) functional activity of drug efflux pumps; and (4) intracellular accumulation of antiretrovirals. Antiretroviral activity was evaluated using cells acutely infected with drug-sensitive/resistant HIV-1 isolates or retroviral vectors, chronically infected cell lines, and syncytium assays. Drug interactions were assessed isobolographically. Activity of efflux pumps was tested using specific fluorochromes. Antitretroviral concentrations were quantitated by HPLC. Results indicated that: (1) the antimalarials (mefloquine > chloroquine) inhibited the replication of drug-sensitive and drug-resistant HIV-1 at therapeutically achievable concentrations and specifically impaired the formation of fusion-competent viral glycoproteins; (2) anti-HIV-1 effects were additive to those of zidovudine and nevirapine, and synergistic to those of lopinavir; (3) the antimalarials (mefloquine > chloroquine) inhibited the P-glycoprotein, multidrug-resistance-associated proteins, and breast-cancer resistance-associated protein; (4) Chloroquine, but not mefloquine, increased lopinavir concentrations in peripheral blood mononuclear cells (PBMCs) by approximately 5 (five)-fold. Thus quinoline antimalarials inhibited HIV-1 replication by a novel mechanism, resulting in additive or synergistic effects in combination with known antiretrovirals. These drugs may also have an impact on the cellular pharmacokinetics of antiretrovirals.
AB - In this study, the effects of the quinoline antimalarials, chloroquine and mefloquine, were tested on: (1) HIV-1 replication; (2) virus response to existing antiretrovirals; (3) functional activity of drug efflux pumps; and (4) intracellular accumulation of antiretrovirals. Antiretroviral activity was evaluated using cells acutely infected with drug-sensitive/resistant HIV-1 isolates or retroviral vectors, chronically infected cell lines, and syncytium assays. Drug interactions were assessed isobolographically. Activity of efflux pumps was tested using specific fluorochromes. Antitretroviral concentrations were quantitated by HPLC. Results indicated that: (1) the antimalarials (mefloquine > chloroquine) inhibited the replication of drug-sensitive and drug-resistant HIV-1 at therapeutically achievable concentrations and specifically impaired the formation of fusion-competent viral glycoproteins; (2) anti-HIV-1 effects were additive to those of zidovudine and nevirapine, and synergistic to those of lopinavir; (3) the antimalarials (mefloquine > chloroquine) inhibited the P-glycoprotein, multidrug-resistance-associated proteins, and breast-cancer resistance-associated protein; (4) Chloroquine, but not mefloquine, increased lopinavir concentrations in peripheral blood mononuclear cells (PBMCs) by approximately 5 (five)-fold. Thus quinoline antimalarials inhibited HIV-1 replication by a novel mechanism, resulting in additive or synergistic effects in combination with known antiretrovirals. These drugs may also have an impact on the cellular pharmacokinetics of antiretrovirals.
KW - ATP-binding cassette
KW - Chloroquine
KW - HIV/malaria co-infection
KW - Intacellular drug concentrations
KW - Mefloquine
KW - Quinoline antimalarials
UR - http://www.scopus.com/inward/record.url?scp=33846416523&partnerID=8YFLogxK
U2 - 10.1002/ddr.20147
DO - 10.1002/ddr.20147
M3 - Article
AN - SCOPUS:33846416523
SN - 0272-4391
VL - 67
SP - 806
EP - 817
JO - Drug Development Research
JF - Drug Development Research
IS - 10
ER -