Anti-HIV effects of chloroquine - Inhibition of viral particle glycosylation and synergism with protease inhibitors

被引:95
作者
Savarino, A
Lucia, MB
Rastrelli, E
Rutella, S
Golotta, C
Morra, E
Tamburrini, E
Perno, CF
Boelaert, JR
Sperber, K
Cauda, R
机构
[1] Univ Cattolica Sacro Cuore, Dept Infect Dis, Lab Viral Immunol, I-00168 Rome, Italy
[2] Univ Cattolica Sacro Cuore, Dept Hematol, Rome, Italy
[3] Mt Sinai Sch Med, Dept Clin Immunol, New York, NY USA
[4] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy
[5] Univ Roma Tor Vergata, Dept Expt Med, Virol Lab, Rome, Italy
[6] AZ Sintjan, Infect Dis Unit, Brugge, Belgium
关键词
antimalarial; protease inhibitors; synergism; P-glycoprotein; multidrug resistance protein-1; developing countries;
D O I
10.1097/00126334-200403010-00002
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Objective: We tested the effects of chloroquine (CQ) on glycosylation of HIV particles and in combination with protease inhibitors (Pis) on HIV replication and on P-glycoprotein (P-gp)/multidrug resistance protein-1 (MRP1). Design: CD4(+) cell lines were infected with laboratory strains and peripheral blood mononuclear cells were infected with primary isolates for evaluation of the anti-HIV effects. Peripheral blood lymphocytes were evaluated for of P-gp and MRP 1 functions. Methods: HIV replication was assessed by enzyme-linked immunosorbent assay. HIV glycosylation was measured by metabolic labeling of viral particles with [3 H] glucosamine. Synergism was tested using isobolograms. P-gp and MRP1 functions were assayed using rhodamine 123 (Ph123) and carboxyfluorescein (CF) efflux assays, respectively. Results: CQ alone inhibited HIV replication and glycosylation in a dose-dependent manner. In combination with indinavir (IDV), ritonavir, or saquinavir (SQV), CQ had a synergistic effect at concentrations found in plasma of subjects receiving malaria prophylaxis. CQ decreased the 50% effective concentration of IDV in primary isolates from Africa and restored the response to IDV or SQV in 3 PI-resistant isolates. CQ increased the block of Rh 123 and CIF efflux activity exerted by Pis. Conclusion: The inhibitory effects of CQ on HIV glycosylation are associated with synergistic effects in combination with Pis. The CQ/PI combination exerts combined inhibitory effects on P-gp and MRP1 function.
引用
收藏
页码:223 / 232
页数:10
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