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

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.